![](https://www.kindai.ac.jp/data/images/professor/906.jpg)
島本 茂(シマモト シゲル)
理工学部 生命科学科 | 准教授 |
Last Updated :2024/08/31
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タンパク質の立体構造と機能の相関。タンパク質の立体構造を参考とした創薬。
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●2021/10/11
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- 生物物理化学 蛋白質工学 熱力学 構造生物学 等温滴定型熱測定 核磁気共鳴法 相互作用解析 蛋白質の立体構造形成 リポカリン プロスタグランジン リポカリン型プロスタグランジンD合成酵素 造血器型プロスタグランジンD合成酵素 生理活性ペプチド 耐熱性エンテロトキシン 前駆体蛋白質 プロウログアニリン
現在の研究分野(キーワード)
タンパク質の立体構造と機能の相関。タンパク質の立体構造を参考とした創薬。
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論文
- Kyona Hiroshima; Nana Sakata; Tadafumi Konogami; Shigeru Shimamoto; Yuji HidakaMolecules 28 23 7754 - 7754 2023年11月Proopiomelanocortin (POMC) is a precursor protein of several peptide hormones, such as ACTH and β-endorphin. Almost all of the peptide hormones in POMC have been drastically investigated in terms of their biological activities. However, the biological activity of the joining peptide region (JP) in POMC is unknown. Therefore, to explore the biological activity of JP, sequence analyses of mammalian POMC were performed. We found an -Arg-Gly-Asp- (RGD) motif in several mammalian species, such as porcine, suggesting that JP has cell adhesion activity. To validate this hypothesis, the cell adhesion activities of the synthetic porcine JP peptides were examined using 293T cells. Cell adhesions were observed in a concentration-dependent manner of the JP peptides. In addition, the JP peptide competitively inhibited cell adhesion to the POMC-coated plates. Moreover, the cell adhesion activity of the joining peptide was inhibited by the addition of EDTA, indicating that the JP peptide mediates the cell adhesion activity via a receptor protein, integrin. Interestingly, a human JP peptide, which possesses an -Arg-Ser-Asp- (RSD) sequence in place of the RGD sequence, exhibited a higher ability in the cell adhesion activity than that of the porcine JP peptide, suggesting that the cell adhesion activity of the joining peptide is developed during the molecular evolution of POMC. In conclusion, our results reveal that the joining peptide in POMC plays an important role during cell adhesion and provide useful information related to signal transduction of nerve peptide hormones derived from POMC.
- Nana Sakata; Yuri Murakami; Mitsuhiro Miyazawa; Shigeru Shimamoto; Yuji HidakaMolecules 28 8 3494 - 3504 2023年04月 [査読有り]
- Masaya Goto; Shinya Yoshino; Kyona Hiroshima; Toru Kawakami; Kaeko Murota; Shigeru Shimamoto; Yuji HidakaMolecules 28 1 1128 - 1142 2023年01月 [査読有り][招待有り]
- Nana Sakata; Ayumi Ogata; Mai Takegawa; Yuri Murakami; Misaki Nishimura; Mitsuhiro Miyazawa; Teruki Hagiwara; Shigeru Shimamoto; Yuji HidakaMolecules 27 2 1 - 13 2022年11月 [査読有り]
- The propeptide sequence assists the correct folding required for the enzymatic activity of cocoonaseNana Sakata; Ayumi Ogata; Mai Takegawa; Nagisa Tajima; Misaki Nishimura; Teruki Hagiwara; Mitsuhiro Miyazawa; Shigeru Shimamoto; Yuji HidakaBiochemical and Biophysical Research Communications 624 35 - 39 2022年10月 [査読有り]
- Shigeru Shimamoto; Yuta Nakahata; Yuji Hidaka; Takuya Yoshida; Tadayasu OhkuboBiomolecular NMR Assignments 2022年04月 [査読有り]
- Shigeru Shimamoto; Yusuke Nakagawa; Yuji Hidaka; Takahiro Maruno; Yuji Kobayashi; Kazuki Kawahara; Takuya Yoshida; Tadayasu Ohkubo; Kosuke Aritake; Mahesh K Kaushik; Yoshihiro UradeBiochemical and biophysical research communications 569 66 - 71 2021年07月 [査読有り]
Prostaglandin D2 (PGD2), an endogenous somnogen, is a unique PG that is secreted into the cerebrospinal fluid. PGD2 is a relatively fragile molecule and should be transported to receptors localized in the basal forebrain without degradation. However, it remains unclear how PGD2 is stably carried to such remote receptors. Here, we demonstrate that the PGD2-synthesizing enzyme, Lipocalin-type prostaglandin D synthase (L-PGDS), binds not only its substrate PGH2 but also its product PGD2 at two distinct binding sites for both ligands. This behaviour implys its PGD2 carrier function. Nevertheless, since the high affinity (Kd = ∼0.6 μM) of PGD2 in the catalytic binding site is comparable to that of PGH2, it may act as a competitive inhibitor, while our binding assay exhibits only weak inhibition (Ki = 189 μM) of the catalytic reaction. To clarify this enigmatic behavior, we determined the solution structure of L-PGDS bound to one substrate analog by NMR and compared it with the two structures: one in the apo form and the other in substrate analogue complex with 1:2 stoichiometry. The structural comparisons showed clearly that open or closed forms of loops at the entrance of ligand binding cavity are regulated by substrate binding to two sites, and that the binding to a second non-catalytic binding site, which apparently substrate concentration dependent, induces opening of the cavity that releases the product. From these results, we propose that L-PGDS is a unique enzyme having a carrier function and a substrate-induced product-release mechanism. - Shigeru Shimamoto; Natsumi Mitsuoka; Saki Takahashi; Toru Kawakami; Yuji HidakaThe protein journal 39 6 711 - 716 2020年12月 [査読有り]
Numerous studies of native proteins have been reported on protein folding in this half century. Recently, post-translationally modified proteins are also focused on protein folding. However, it is still difficult to prepare such types of proteins because it requires not only the chemical but also the recombinant techniques. Native chemical ligation (NCL) is a powerful technique for producing target proteins when combined with recombinant techniques, such as expressed protein ligation (EPL). NCL basically requires an N-terminal peptide with a thioester and a C-terminal peptide which should possess a Cys residue at the N-terminus. Numerous efforts have been made to prepare N-terminal peptides carrying a thioester or a derivative thereof. However, a method for preparing C-terminal Cys-peptides with post-translational modifications has not been well developed, making it difficult to prepare such C-terminal Cys-peptides, except for chemical syntheses or enzymatic digestion. We report here on the development of a convenient technique that involves acid hydrolysis at the -Asp-Cys- sequence, to effectively obtain a C-terminal peptide fragment that can be used for any protein synthesis when combined with EPL, even under denatured conditions. Thus, this chemical digestion strategy permits the NCL strategy to be dramatically accelerated for protein syntheses in which post-translational modifications, such as glycosylation, phosphorylation, etc. are involved. In addition, this method should be useful to prepare the post-translationally modified proteins for protein folding. - Shigeru Shimamoto; Mayu Fukutsuji; Toi Osumi; Masaya Goto; Hiroshi Toyoda; Yuji HidakaMolecules (Basel, Switzerland) 25 20 2020年10月 [査読有り]
Heat-stable enterotoxin (STa) produced by enterotoxigenic E. coli causes acute diarrhea and also can be used as a specific probe for colorectal cancer cells. STa contains three intra-molecular disulfide bonds (C1-C4, C2-C5, and C3-C6 connectivity). The chemical synthesis of STa provided not only the native type of STa but also a topological isomer that had the native disulfide pairings. Interestingly, the activity of the topological isomer was approximately 1/10-1/2 that of the native STa. To further investigate the bioactive conformation of this molecule and the regulation of disulfide-coupled folding during its chemical syntheses, we examined the folding mechanism of STa that occurs during its chemical synthesis. The folding intermediate of STa with two disulfide bonds (C1-C4 and C3-C6) and two Cys(Acm) residues, the precursor peptide, was treated with iodine to produce a third disulfide bond under several conditions. The topological isomer was predominantly produced under all conditions tested, along with trace amounts of the native type of STa. In addition, NMR measurements indicated that the topological isomer has a left-handed spiral structure similar to that of the precursor peptide, while the native type of STa had a right-handed spiral structure. These results indicate that the order of the regioselective formation of disulfide bonds is important for the regulation of the final conformation of disulfide-rich peptides in chemical synthesis. - Kenji Yamamoto; Osamu Ishibashi; Keisuke Sugiura; Miki Ubatani; Masaya Sakaguchi; Masatoshi Nakatsuji; Shigeru Shimamoto; Masanori Noda; Susumu Uchiyama; Yuma Fukutomi; Shigenori Nishimura; Takashi InuiScientific reports 9 1 1503 - 1503 2019年02月 [査読有り]
Several dog allergens cause allergic reactions in humans worldwide. Seven distinct dog allergens, designated Canis familiaris allergen 1 to 7 (Can f 1-Can f 7), have been identified thus far. Can f 6 shows high sequence similarity and cross-reactivity with Fel d 4 and Equ c 1, major cat and horse allergens, respectively. This study was conducted on the allergenic epitopes of Can f 6 based on its structural characterization. We demonstrated that sera from 18 out of 38 (47%) dog-sensitized patients reacted to recombinant Can f 6 protein (rCan f 6). We then determined the crystal structure of rCan f 6 by X-ray crystallography, which exhibited a conserved tertiary structural architecture found in lipocalin family proteins. Based on the tertiary structure and sequence similarities with Fel d 4 and Equ c 1, we predicted three IgE-recognizing sites that are possibly involved in cross-reactivity. Substituting three successive amino acids in these sites to triple alanine decreased IgE reactivity to the allergen. However, the degree of reduction in IgE reactivity largely depended on the site mutated and the serum used, suggesting that Can f 6 is a polyvalent allergen containing multiple epitopes and Can f 6-reactive sera contain varied amounts of IgE recognising individual Can f 6 epitopes including those predicted in this study. We also demonstrated that the predicted epitopes are partly involved in IgE cross-reactivity to Fel d 4. Interestingly, the effect of the mutation depended on whether the protein was structured or denatured, indicating that the bona fide tertiary structure of Can f 6 is essential in determining its IgE epitopes. - Zheng Y; Shimamoto S; Maruno T; Kobayashi Y; Matsuura Y; Kawahara K; Yoshida T; Ohkubo TBiochemical and biophysical research communications 509 2 590 - 595 2019年02月 [査読有り]
The Hepatitis C virus (HCV) core protein plays a crucial role in the development of chronic liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Its involvement in these diseases is reportedly abolished by a knockout of the proteasome activator PA28γ gene in transgenic mice, suggesting an interaction between the core protein and the PA28γ-proteasome system. This study found a direct interaction between the N-terminal 1-71 fragment of HCV core protein (Core71) and PA28γ in vitro, and that this interaction was found to enhance PA28γ-20S proteasome complex formation. While 20S proteasome activity was increased by PA28γ, it was significantly reduced by Core71 attachment in a dose-dependent manner. These results suggest that the Core-PA28γ interaction has an important role in regulating 20S proteasome activity and furthers our understanding of the pathogenesis of HCV. - Shubin Qin; Shigeru Shimamoto; Takahiro Maruno; Yuji Kobayashi; Kazuki Kawahara; Takuya Yoshida; Tadayasu OhkuboBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 468 1-2 234 - 239 2015年12月 [査読有り]
Lipocalin-type prostaglandin D synthase (L-PGDS) is one of the most abundant proteins in human cerebrospinal fluid (CSF) with dual functions as a prostaglandin D-2 (PGD(2)) synthase and a transporter of lipophilic ligands. Recent studies revealed that L-PGDS plays important roles in protecting against various neuronal diseases induced by reactive oxygen species (ROS). However, the molecular mechanisms of such protective actions of L-PGDS remain unknown. In this study, we conducted thermodynamic and nuclear magnetic resonance (NMR) analyses, and demonstrated that L-PGDS binds to nicotinamide coenzymes, including NADPH, NADP(+), and NADH. Although a hydrophilic ligand is not common for L-PGDS, these ligands, especially NADPH showed specific interaction with L-PGDS at the upper pocket of its ligand-binding cavity with an unusually bifurcated shape. The binding affinity of L-PGDS for NADPH was comparable to that previously reported for NADPH oxidases and NADPH in vitro. These results suggested that L-PGDS potentially attenuates the activities of NADPH oxidases through interaction with NADPH. Given that NADPH is the substrate for NADPH oxidases that play key roles in neuronal cell death by generating excessive ROS, these results imply a novel linkage between L-PGDS and ROS. (C) 2015 Elsevier Inc. All rights reserved. - Shimamoto S; Maruo H; Yoshida T; Ohkubo TBiomolecular NMR assignments 8 1 129 - 32 2014年04月 [査読有り]
Lipocalin-type Prostaglandin D synthase (L-PGDS) acts as the PGD2-synthesizing enzyme in the brain of various mammalian species. It belongs to the lipocalin superfamily and is the first member of this family to be recognized as an enzyme. Although the solution and crystal structure of L-PGDS has been determined to understand the molecular mechanism of catalytic reaction, the structural analysis of L-PGDS in complex with its substrate remains to be performed. Here, we present the nearly complete assignment of the backbone and side chain resonances of L-PGDS/substrate analog (U-46619) complex. This study lays the essential basis for further understanding the substrate recognition mechanism of L-PGDS. - Chemical methods for producing disulfide bonds in peptides and proteins to study folding regulation.Masaki Okumura; Shigeru Shimamoto; Yuji HidakaCurrent protocols in protein science 76 76 28.7.1-28.7.13 - 13 2014年04月 [査読有り]
Disulfide bonds play a critical role in the folding of secretory and membrane proteins. Oxidative folding reactions of disulfide bond-containing proteins typically require several hours or days, and numerous misbridged disulfide isomers are often observed as intermediates. The rate-determining step in refolding is thought to be the disulfide-exchange reaction from nonnative to native disulfide bonds in folding intermediates, which often precipitate during the refolding process because of their hydrophobic properties. To overcome this, chemical additives or a disulfide catalyst, protein disulfide isomerase (PDI), are generally used in refolding experiments to regulate disulfide-coupled peptide and protein folding. This unit describes such methods in the context of the thermodynamic and kinetic control of peptide and protein folding, including (1) regulation of disulfide-coupled peptides and protein folding assisted by chemical additives, (2) reductive unfolding of disulfide-containing peptides and proteins, and (3) regulation of disulfide-coupled peptide and protein folding using PDI. - Shigeru Shimamoto; Hidekazu Katayama; Masaki Okumura; Yuji HidakaCurrent protocols in protein science 76 76 28.8.1-28.8.28 - 28.8.28 2014年04月 [査読有り]
Disulfide-bond formation plays an important role in the stabilization of the native conformation of peptides and proteins. In the case of multidisulfide-containing peptides and proteins, numerous folding intermediates are produced, including molecules that contain non-native and native disulfide bonds during in vitro folding. These intermediates can frequently be trapped covalently during folding and subsequently analyzed. The structural characterization of these kinetically trapped disulfide intermediates provides a clue to understanding the oxidative folding pathway. To investigate the folding of disulfide-containing peptides and proteins, in this unit, chemical methods are described for regulating regioselective disulfide formation (1) by using a combination of several types of thiol protecting groups, (2) by incorporating unique SeCys residues into a protein or peptide molecule, and (3) by combining with post-translational modification. - Yuji Hidaka; Shigeru ShimamotoBiomolecular concepts 4 6 597 - 604 2013年12月 [査読有り]
Disulfide-containing proteins are ideal models for studies of protein folding as the folding intermediates can be observed, trapped, and separated by HPLC during the folding reaction. However, regulating or analyzing the structures of folding intermediates of peptides and proteins continues to be a difficult problem. Recently, the development of several techniques in peptide chemistry and biotechnology has resulted in the availability of some powerful tools for studying protein folding in the context of the structural analysis of native, mutant proteins, and folding intermediates. In this review, recent developments in the field of disulfide-coupled peptide and protein folding are discussed, from the viewpoint of chemical and biotechnological methods, such as analytical methods for the detection of disulfide pairings, chemical methods for disulfide bond formation between the defined Cys residues, and applications of diselenide bonds for the regulation of disulfide-coupled peptide and protein folding. - Masaki Okumura; Shigeru Shimamoto; Takeyoshi Nakanishi; Yu-ichiro Yoshida; Tadafumi Konogami; Shogo Maeda; Yuji HidakaFEBS letters 586 21 3926 - 30 2012年11月 [査読有り]
In vitro folding of disulfide-containing proteins is generally regulated by redox molecules, such as glutathione. However, the role of the cross-disulfide-linked species formed between the redox molecule and the protein as a folding intermediate in the folding mechanism is poorly understood. In the present study, we investigated the effect of the charge on a redox molecule on disulfide-coupled protein folding. Several types of aliphatic thiol compounds including glutathione were examined for the folding of disulfide-containing-proteins, such as lysozyme and prouroguanylin. The results indicate that the positive charge and its dispersion play a critical role in accelerating disulfide-coupled protein folding. - Masaki Okumura; Shigeru Shimamoto; Yuji HidakaThe FEBS journal 279 13 2283 - 95 2012年07月 [査読有り]
Investigations of protein folding have largely involved studies using disulfide-containing proteins, as disulfide-coupled folding of proteins permits the folding intermediates to be trapped and their conformations determined. Over the last decade, a combination of new biotechnical and chemical methodology has resulted in a remarkable acceleration in our understanding of the mechanism of disulfide-coupled protein folding. In particular, expressed protein ligation, a combination of native chemical ligation and an intein-based approach, permits specifically labeled proteins to be easily produced for studies of protein folding using biophysical methods, such as NMR spectroscopy and X-ray crystallography. A method for regio-selective formation of disulfide bonds using chemical procedures has also been established. This strategy is particularly relevant for the study of disulfide-coupled protein folding, and provides us not only with the native conformation, but also the kinetically trapped topological isomer with native disulfide bonds. Here we review recent developments and applications of biotechnical and chemical methods to investigations of disulfide-coupled peptide and protein folding. Chemical additives designed to accelerate correct protein folding and to avoid non-specific aggregation are also discussed. - Ayano Fukuhara; Hidemitsu Nakajima; Yuya Miyamoto; Katsuaki Inoue; Satoshi Kume; Young-Ho Lee; Masanori Noda; Susumu Uchiyama; Shigeru Shimamoto; Shigenori Nishimura; Tadayasu Ohkubo; Yuji Goto; Tadayoshi Takeuchi; Takashi InuiJournal of controlled release : official journal of the Controlled Release Society 159 1 143 - 50 2012年04月 [査読有り]
Lipocalin-type prostaglandin D synthase (L-PGDS) is a member of the lipocalin superfamily and a secretory lipid-transporter protein, which binds a wide variety of hydrophobic small molecules. Here we show the feasibility of a novel drug delivery system (DDS), utilizing L-PGDS, for poorly water-soluble compounds such as diazepam (DZP), a major benzodiazepine anxiolytic drug, and 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and anticonvulsant. Calorimetric experiments revealed for both compounds that each L-PGDS held three molecules with high binding affinities. By mass spectrometry, the 1:3 complex of L-PGDS and NBQX was observed. L-PGDS of 500μM increased the solubility of DZP and NBQX 7- and 2-fold, respectively, compared to PBS alone. To validate the potential of L-PGDS as a drug delivery vehicle in vivo, we have proved the prospective effects of these compounds via two separate delivery strategies. First, the oral administration of a DZP/L-PGDS complex in mice revealed an increased duration of pentobarbital-induced loss of righting reflex. Second, the intravenous treatment of ischemic gerbils with NBQX/L-PGDS complex showed a protective effect on delayed neuronal cell death at the hippocampal CA1 region. We propose that our novel DDS could facilitate pharmaceutical development and clinical usage of various water-insoluble compounds. - 島本 茂; 吉田 卓也; 大久保 忠恭薬学雑誌. 乙号 131 11 1575 - 1581 The Pharmaceutical Society of Japan 2011年 [査読有り][招待有り]
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is a multi functional protein acting as a PGD2 synthesizing enzyme, a transporter or scavenger of various lipophilic ligands, and an amyloid β chaperon in the brain. L-PGDS is a member of the lipocalin superfamily and has the ability to bind various lipophilic molecules such as prostanoid, retinoid, bile pigment, and amyloid β peptide. However, the molecular mechanism for a wide variety of ligand binding has not been well understood. In this study, we determined by NMR the structure of recombinant mouse L-PGDS and L-PGDS/PGH2 analog complex. L-PGDS has the typical lipocalin fold, consisting of an eight-stranded β-barrel and a long α-helix. The interior of the barrel formed a hydrophobic cavity opening to the upper end of the barrel, the size of which was larger than those of other lipocalins and the cavity contained two pockets. Kinetic studies and molecular docking studies based on the result of NMR titration experiments provide the direct evidence for two binding sites for PGH2 and retinoic acid in the large cavity of L-PGDS. Structural comparison of L-PGDS/U-46619 complex with apo-L-PGDS showed that the H2-helix, CD-loop, and EF-loop located at the upper end of the β-barrel change the conformation to cover the entry of the cavity upon U-46619 binding. These results indicated that the two binding sites in the large cavity and induced fit mechanism were responsible for the broad ligand specificity of L-PGDS. - Kayoko Hayashihara; Susumu Uchiyama; Shigeru Shimamoto; Shouhei Kobayashi; Miroslav Tomschik; Hidekazu Wakamatsu; Daisuke No; Hiroki Sugahara; Naoto Hori; Masanori Noda; Tadayasu Ohkubo; Jordanka Zlatanova; Sachihiro Matsunaga; Kiichi FukuiThe Journal of biological chemistry 285 9 6498 - 507 2010年02月 [査読有り]
In higher eukaryotic cells, DNA molecules are present as chromatin fibers, complexes of DNA with various types of proteins; chromatin fibers are highly condensed in metaphase chromosomes during mitosis. Although the formation of the metaphase chromosome structure is essential for the equal segregation of replicated chromosomal DNA into the daughter cells, the mechanism involved in the organization of metaphase chromosomes is poorly understood. To identify proteins involved in the formation and/or maintenance of metaphase chromosomes, we examined proteins that dissociated from isolated human metaphase chromosomes by 0.4 m NaCl treatment; this treatment led to significant chromosome decondensation, but the structure retained the core histones. One of the proteins identified, HP1-BP74 (heterochromatin protein 1-binding protein 74), composed of 553 amino acid residues, was further characterized. HP1-BP74 middle region (BP74Md), composed of 178 amino acid residues (Lys(97)-Lys(274)), formed a chromatosome-like structure with reconstituted mononucleosomes and protected the linker DNA from micrococcal nuclease digestion by approximately 25 bp. The solution structure determined by NMR revealed that the globular domain (Met(153)-Thr(237)) located within BP74Md possesses a structure similar to that of the globular domain of linker histones, which underlies its nucleosome binding properties. Moreover, we confirmed that BP74Md and full-length HP1-BP74 directly binds to HP1 (heterochromatin protein 1) and identified the exact sites responsible for this interaction. Thus, we discovered that HP1-BP74 directly binds to HP1, and its middle region associates with linker DNA at the entry/exit site of nucleosomal DNA in vitro. - Yuya Miyamoto; Shigenori Nishimura; Katsuaki Inoue; Shigeru Shimamoto; Takuya Yoshida; Ayano Fukuhara; Mao Yamada; Yoshihiro Urade; Naoto Yagi; Tadayasu Ohkubo; Takashi InuiJournal of structural biology 169 2 209 - 18 2010年02月 [査読有り]
Lipocalin-type prostaglandin D synthase (L-PGDS) acts as both a PGD(2) synthase and an extracellular transporter for small lipophilic molecules. From a series of biochemical studies, it has been found that L-PGDS has an ability to bind a variety of lipophilic ligands such as biliverdin, bilirubin and retinoids in vitro. Therefore, we considered that it is necessary to clarify the molecular structure of L-PGDS upon binding ligand in order to understand the physiological relevance of L-PGDS as a transporter protein. We investigated a molecular structure of L-PGDS/biliverdin complex by small-angle X-ray scattering (SAXS) and multi-dimensional NMR measurements, and characterized the binding mechanism in detail. SAXS measurements revealed that L-PGDS has a globular shape and becomes compact by 1.3A in radius of gyration on binding biliverdin. NMR experiments revealed that L-PGDS possessed an eight-stranded antiparallel beta-barrel forming a central cavity. Upon the titration with biliverdin, some cross-peaks for residues surrounding the cavity and EF-loop and H2-helix above the beta-barrel shifted, and the intensity of other cross-peaks decreased with signal broadenings in (1)H-(15)N heteronuclear single quantum coherence spectra. These results demonstrate that L-PGDS holds biliverdin within the beta-barrel, and the conformation of the loop regions above the beta-barrel changes upon binding biliverdin. Through such a conformational change, the whole molecule of L-PGDS becomes compact. - Daisuke Irikura; Kosuke Aritake; Nanae Nagata; Toshihiko Maruyama; Shigeru Shimamoto; Yoshihiro UradeThe Journal of biological chemistry 284 12 7623 - 30 2009年03月 [査読有り]
We report here that 4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine (AT-56) is an orally active and selective inhibitor of lipocalin-type prostaglandin (PG) D synthase (L-PGDS). AT-56 inhibited human and mouse L-PGDSs in a concentration (3-250 microm)-dependent manner but did not affect the activities of hematopoietic PGD synthase (H-PGDS), cyclooxygenase-1 and -2, and microsomal PGE synthase-1. AT-56 inhibited the L-PGDS activity in a competitive manner against the substrate PGH(2) (K(m) = 14 microm) with a K(i) value of 75 microm but did not inhibit the binding of 13-cis-retinoic acid, a nonsubstrate lipophilic ligand, to L-PGDS. NMR titration analysis revealed that AT-56 occupied the catalytic pocket, but not the retinoid-binding pocket, of L-PGDS. AT-56 inhibited the production of PGD(2) by L-PGDS-expressing human TE-671 cells after stimulation with Ca(2+) ionophore (5 microm A23187) with an IC(50) value of about 3 microm without affecting their production of PGE(2) and PGF(2alpha) but had no effect on the PGD(2) production by H-PGDS-expressing human megakaryocytes. Orally administered AT-56 (<30 mg/kg body weight) decreased the PGD(2) production to 40% in the brain of H-PGDS-deficient mice after a stab wound injury in a dose-dependent manner without affecting the production of PGE(2) and PGF(2alpha) and also suppressed the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice. - Shigeru Shimamoto; Takuya Yoshida; Takashi Inui; Keigo Gohda; Yuji Kobayashi; Ko Fujimori; Toshiharu Tsurumura; Kosuke Aritake; Yoshihiro Urade; Tadayasu OhkuboThe Journal of biological chemistry 282 43 31373 - 9 2007年10月 [査読有り]
Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), an endogenous somnogen and nociceptive modulator, in the brain. L-PGDS is a member of the lipocalin superfamily and binds lipophilic substances, such as retinoids and bile pigments, suggesting that L-PGDS is a dual functional protein acting as a PGD(2)-synthesizing enzyme and a transporter for lipophilic ligands. In this study we determined by NMR the three-dimensional structure of recombinant mouse L-PGDS with the catalytic residue Cys-65. The structure of L-PGDS exhibited the typical lipocalin fold, consisting of an eight-stranded, antiparallel beta-barrel and a long alpha-helix associated with the outer surface of the barrel. The interior of the barrel formed a hydrophobic cavity opening to the upper end of the barrel, the size of which was larger than those of other lipocalins, and the cavity contained two pockets. Molecular docking studies, based on the result of NMR titration experiments with retinoic acid and PGH(2) analog, revealed that PGH(2) almost fully occupied the hydrophilic pocket 1, in which Cys-65 was located and all-trans-retinoic acid occupied the hydrophobic pocket 2, in which amino acid residues important for retinoid binding in other lipocalins were well conserved. Mutational and kinetic studies provide the direct evidence for the PGH(2) binding mode. These results indicated that the two binding sites for PGH(2) and retinoic acid in the large cavity of L-PGDS were responsible for the broad ligand specificity of L-PGDS and the non-competitive inhibition of L-PGDS activity by retinoic acid.
MISC
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- Mayu Fukutsuji; Aman L. Maharjan; Toi Osumi; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 118 (3) 508A -508A 2020年02月
- Yuji Hidaka; Hayato Ueda; Shigeru Shimamoto BIOPHYSICAL JOURNAL 118 (3) 59A -59A 2020年02月
- Toi Osumi; Aman L. Maharjan; Mayu Fukutsuji; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 118 (3) 510A -511A 2020年02月
- Mai Takegawa; Tsubasa Tagawa; Ayumi Ogata; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 118 (3) 532A -532A 2020年02月
- FUKUTSUJI Mayu; MAHARJAN Aman Lall; OSUMI Toi; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2019 2020年
- TAKEGAWA Mai; TAGAWA Tsubasa; OGATA Ayumi; MIYAZAWA Mitsuhiro; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2019 2020年
- TAGAWA Tsubasa; HAGIWARA Teruki; MIYAZAWA Mitsuhiro; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2019 2020年
- MAHARJAN Aman Lall; OSUMI Toi; FUKUTSUJI Mayu; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2019 2020年
- 島本茂; 中川悠介; 日高雄二; 丸野孝浩; 小林祐次; 河原一樹; 吉田卓也; 大久保忠恭; 有竹浩介; 裏出良博 日本細胞生物学会大会(Web) 71st 2019年
- 東野貴大; 島本茂; 日高雄二 日本細胞生物学会大会(Web) 71st 2019年
- 岩壁一樹; 鳥居希美; 島本茂; 加川尚; 日高雄二 日本細胞生物学会大会(Web) 71st 2019年
- 上田隼; 島本茂; 日高雄二 日本細胞生物学会大会(Web) 71st 2019年
- 田川翼; 萩原央記; 宮澤光博; 島本茂; 日高雄二 日本細胞生物学会大会(Web) 71st 2019年
- 岡祐希; 岩壁一樹; 鳥居希美; 加川尚; 日高雄二; 島本茂 熱測定討論会講演要旨集 55th 2019年
- UEDA Hayato; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2018 2019年
- TAGAWA Tsubasa; HAGIWARA Teruki; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2018 2019年
- IMAMURA Mizuho; KANEMURA Shingo; OKUMURA Masaki; YAMAGUCHI Hiroshi; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2018 2019年
- Yuji Hidaka; Saya Nishihara; Kenta Mori; Shigeru Shimamoto BIOPHYSICAL JOURNAL 114 (3) 54A -54A 2018年02月
- Mizuho Imamura; Shingo Kanemura; Masaki Okumura; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 114 (3) 78A -78A 2018年02月
- Nagisa Tajima; Mitsuhiro Miyazawa; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 114 (3) 581A -581A 2018年02月
- Kimi Torii; Yuji Hidaka; Shigeru Shimamoto BIOPHYSICAL JOURNAL 114 (3) 51A -51A 2018年02月
- Shigeru Shimamoto; Keisuke Asada; Yuji Hidaka BIOPHYSICAL JOURNAL 114 (3) 581A -581A 2018年02月
- 田村和朗; 長尾哲二; 南武志; 日高雄二; 辻内俊文; 巽純子; 福嶋伸之; 加川尚; 西郷和真; 島本茂; 川下理日人; 福岡和也; 中川和彦 日本人類遺伝学会大会プログラム・抄録集 63rd 2018年
- 山本賢史; 石橋宰; 杉浦慶亮; 姥谷美樹; 中辻匡俊; 島本茂; 野田勝紀; 内山進; 福冨友馬; 西村重徳; 乾隆 日本蛋白質科学会年会プログラム・要旨集 18th 2018年
- 小林優真; 奥村正樹; 奥村正樹; 島本茂; 稲葉謙次; 山口宏; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 18th 2018年
- 秋山佳範; 下地真広; 島本茂; 寺岡佳晃; 寺岡佳晃; 乾隆 日本生化学会大会(Web) 91st 2018年
- IMAMURA Mizuho; KANEMURA Shingo; OKUMURA Masaki; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2017 2018年
- TORII Kimi; MARUNO Takahiro; KOBAYASHI Yuji; HIDAKA Yuji; SHIMAMOTO Shigeru Peptide Science 2017 2018年
- NISHIHARA Saya; TOYAMA Kosuke; MORI Kenta; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2017 2018年
- MORI Kenta; TOYAMA Kosuke; NISHIHARA Saya; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2017 2018年
- Natsumi Mitsuoka; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 112 (3) 47A -47A 2017年02月
- Saya Nishihara; Kosuke Toyama; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 112 (3) 50A -50A 2017年02月
- Keisuke Asada; Shigeru Shimamoto; Tomohiro Oonoki; Takahiro Maruno; Yuji Kobayashi; Kosuke Aritake; Yoshihiro Urade; Yuji Hidaka BIOPHYSICAL JOURNAL 112 (3) 494A -494A 2017年02月
- Yuji Hidaka; Ryosuke Nishimura; Shigeru Shimamoto BIOPHYSICAL JOURNAL 112 (3) 57A -57A 2017年02月
- Sumika Futori; Satomi Higashigawa; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 112 (3) 51A -51A 2017年02月
- Shigeru Shimamoto; Yusuke Nakagawa; Takahiro Maruno; Yuji Kobayashi; Kosuke Aritake; Urade Yoshihiro; Yuji Hidaka BIOPHYSICAL JOURNAL 112 (3) 494A -495A 2017年02月
- 小林優真; 奥村正樹; 奥村正樹; 島本茂; 牧野晃大; 稲葉謙次; 山口宏; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 17th 2017年
- 小林優真; 奥村正樹; 奥村正樹; 島本茂; 稲葉謙次; 山口宏; 日高雄二 日本生化学会大会(Web) 90th 2017年
- Shigeru Shimamoto; Yuta Nakahata; Yusuke Nakagawa; Yutaro Fukuda; Kosuke Aritake; Yoshihiro Urade; Yuji Hidaka BIOPHYSICAL JOURNAL 110 (3) 379A -379A 2016年02月
- Kosuke Toyama; Masaki Okumura; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 110 (3) 210A -210A 2016年02月
- Yuji Hidaka; Takeyosi Nakanishi; Shigeru Shimamoto BIOPHYSICAL JOURNAL 110 (3) 210A -210A 2016年02月
- Yusuke Nakagawa; Shigeru Shimamoto; Yutaro Fukuda; Takahiro Maruno; Yuji Kobayashi; Tadayasu Ohkubo; Kousuke Aritake; Yoshihiro Urade; Yuji Hidaka BIOPHYSICAL JOURNAL 110 (3) 541A -542A 2016年02月
- Kenta Hattori; Masaki Okumura; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 110 (3) 389A -389A 2016年02月
- 浅田恵佑; 島本茂; 大野木友大; 丸野孝浩; 小林祐次; 有竹浩介; 裏出良博; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 16th 2016年
- 牧野晃大; 奥村正樹; 島本茂; 服部健太; 李映昊; 杉木俊彦; 稲葉謙次; 山口宏; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 16th 2016年
- NISHIHARA Saya; TOYAMA Kosuke; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2016 2016年
- HATTORI Kenta; OKUMURA Masaki; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2015 2016年
- TOYAMA Kosuke; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2015 2016年
- MORI Kenta; TOYAMA Kosuke; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2016 2016年
- TAJIMA Nagisa; SHIMAMOTO Shigeru; MIYAZAWA Mitsuhiro; HIDAKA Yuji Peptide Science 2016 2016年
- MITSUOKA Natsumi; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2016 2016年
- 中川悠介; 島本茂; 福田裕太郎; 丸野孝浩; 小林祐次; 大久保忠恭; 有竹浩介; 裏出良博; 日高雄二 熱測定討論会講演要旨集 51st 2015年
- 沖大也; 島本茂; 秦殊斌; 加藤信幸; 元岡大祐; 中村昇太; 河原一樹; 吉田卓也; 大久保忠恭 日本結晶学会年会講演要旨集 2015 2015年
- 森本幸生; 山口宏; 細川桂一; 村上琢人; 喜田昭子; 海野昌喜; 久留一郎; 茶竹俊行; 柳澤泰任; 藤原悟; 田中伊知朗; 日高雄二; 島本茂; 藤原充俊; 中西健祥 KURRI-KR (200) 2015年
- YOKOYAMA Yukihito; OKUMURA Masaki; SHIMAMOTO Shigeru; YAMAGUCHI Hiroshi; HIDAKA Yuji Peptide Science 2014 2015年
- Yuji Hidaka; Kana Ohshige; Takeyoshi Nakanishi; Shigeru Shimamoto BIOPHYSICAL JOURNAL 108 (2) 515A -516A 2015年01月
- Yuta Nakahata; Shigeru Shimamoto; Tadayasu Ohkubo; Kosuke Aritake; Yoshihiro Urade; Yuji Hidaka BIOPHYSICAL JOURNAL 108 (2) 510A -510A 2015年01月
- Shigeru Shimamoto; Yutaro Fukuda; Takahiro Maruno; Yuji Kobayashi; Tadayasu Ohkubo; Kosuke Aritake; Yoshihiro Urade; Yuji Hidaka BIOPHYSICAL JOURNAL 108 (2) 513A -513A 2015年01月
- 中畑雄太; 島本茂; 福田裕太郎; 大久保忠恭; 有竹浩介; 裏出良博; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 14th 2014年
- 島本茂; 福田裕太郎; 日高雄二; 丸野孝浩; 小林祐次; 有竹浩介; 裏出良博; 大久保忠恭 熱測定討論会講演要旨集 50th 2014年
- 中畑雄太; 島本茂; 福田裕太郎; 大久保忠恭; 有竹浩介; 裏出良博; 日高雄二 生体機能と創薬シンポジウム要旨集 2014 2014年
- 福田裕太郎; 島本茂; 丸野孝浩; 小林祐次; 大久保忠恭; 有竹浩介; 裏出良博; 日高雄二 生体機能と創薬シンポジウム要旨集 2014 2014年
- 大重佳奈; 島本茂; 佐伯政俊; 日高雄二 生体機能と創薬シンポジウム要旨集 2014 2014年
- 鄭洋; 杉本智美; 丸野孝浩; 島本茂; 松浦善治; 小林祐次; 大久保忠恭 日本薬学会年会要旨集(CD-ROM) 134th 2014年
- 藤原充俊; 宮澤光博; 島本茂; 日高雄二 生体機能と創薬シンポジウム要旨集 2014 2014年
- 中西健祥; 奥村正樹; 島本茂; 日高雄二 生体機能と創薬シンポジウム要旨集 2014 2014年
- 孝田和輝; 此上祥史; 島本茂; 日高雄二 生体機能と創薬シンポジウム要旨集 2014 2014年
- 横山至仁; 奥村正樹; 島本茂; 山口宏; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 14th 2014年
- 有竹浩介; 有竹浩介; 永田奈々恵; 伊藤奈々子; 阪田真澄; 島本茂; 裏出良博; 裏出良博 日本生化学会大会(Web) 87th 2014年
- NAKANISHI Takeyoshi; OKUMURA Masaki; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2013 2014年
- FUKUDA Yutaro; MARUNO Takahiro; KOBAYASHI Yuji; OHKUBO Tadayasu; ARITAKE Kosuke; URADE Yoshihiro; HIDAKA Yuji; SHIMAMOTO Shigeru Peptide Science 2013 2014年
- OHSHIGE Kana; IWAKIRI Atsuro; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2013 2014年
- FUJIWARA Mitsutoshi; MIYAZAWA Mitsuhiro; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2013 2014年
- FUKUMOTO Shiori; YOSHIDA Yuichiro; MAEKAWA Takuma; OKUMURA Masaki; YAMAGUCHI Hiroshi; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2013 2014年
- Yuji Hidaka; Tadafumi Konogami; Shigeru Shimamoto BIOPHYSICAL JOURNAL 106 (2) 470A -470A 2014年01月
- Shigeru Shimamoto; Tadayasu Ohkubo; Kosuke Aritake; Yoshihiro Urade; Yuji Hidaka BIOPHYSICAL JOURNAL 106 (2) 48A -48A 2014年01月
- Shiori Fukumoto; Yuichiro Yoshida; Takuma Maekawa; Masaki Okumura; Hiroshi Yamaguchi; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 106 (2) 472A -472A 2014年01月
- Takeyoshi Nakanishi; Masaki Okumura; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 106 (2) 472A -472A 2014年01月
- Yutaro Fukuda; Takahiro Maruno; Yuji Kobayashi; Tadayasu Ohkubo; Kosuke Aritake; Yoshihiro Urade; Yuji Hidaka; Shigeru Shimamoto BIOPHYSICAL JOURNAL 106 (2) 675A -676A 2014年01月
- Kana Ohshige; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 106 (2) 673A -673A 2014年01月
- Mitsutoshi Fujiwara; Mitsuhiro Miyazawa; Shigeru Shimamoto; Yuji Hidaka BIOPHYSICAL JOURNAL 106 (2) 677A -677A 2014年01月
- 日高雄二; 中西健祥; 奥村正樹; 島本茂 日本蛋白質科学会年会プログラム・要旨集 13th 2013年
- 福本栞; 吉田祐一朗; 前川拓摩; 奥村正樹; 島本茂; 日高雄二 日本蛋白質科学会年会プログラム・要旨集 13th 2013年
- KONOGAMI Tadafumi; WATANABE Kenji; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2012 2013年
- MAEKAWA Takuma; FUKUMOTO Shiori; YOSHIDA Yu-ichiro; OKUMURA Masaki; YAMAGUCHI Hiroshi; SHIMAMOTO Shigeru; HIDAKA Yuji Peptide Science 2012 2013年
- YOSHIDA Yu-ichiro; OKUMURA Masaki; SHIMAMOTO Shigeru; HASEGAWA Kyohei; YAMAGUCHI Hiroshi; HIDAKA Yuji Peptide Science 2011 2012年
- KONOGAMI Tadafumi; WATANABE Kenji; SHIMAMOTO Shigeru; BASAK Ajoy; YAMAGUCHI Hiroshi; HIDAKA Yuji Peptide Science 2011 2012年
- Shigeru Shimamoto; Takuya Yoshida; Yuya Miyamoto; Takashi Inui; Kosuke Aritake; Yoshihiro Urade; Tadayasu Ohkubo BIOPHYSICAL JOURNAL 102 (3) 252A -252A 2012年01月
- Yu-ichiro Yoshida; Masaki Okumura; Shigeru Shimamoto; Hiroshi Yamaguchi; Yuji Hidaka BIOPHYSICAL JOURNAL 102 (3) 56A -56A 2012年01月
- Tadafumi Konogami; Kenji Watanabe; Shigeru Shimamoto; Ajoy Basak; Hiroshi Yamaguchi; Yuji Hidaka BIOPHYSICAL JOURNAL 102 (3) 45A -45A 2012年01月
- 福原彩乃; 中嶋秀満; 井上勝晶; 宮本優也; 島本茂; 大久保忠恭; 西村重徳; 竹内正吉; 乾隆 Drug Delivery System 25 (3) 2010年
- 加藤信幸; 島本茂; 島本茂; 吉田卓也; QIN Shubin; 小林祐次; 有竹浩介; 裏出良博; 大久保忠恭 Abstracts. Annual Meeting of the NMR Society of Japan 49th 2010年
- Y. Miyamoto; S. Nishimura; K. Inoue; T. Yoshida; S. Shimamoto; A. Fukuhara; M. Yamada; N. Yagi; T. Ohkubo; T. Inui FEBS JOURNAL 275 172 -172 2008年06月
- Shigeru Shimamoto; Takuya Yoshida; Takashi Inui; Keigo Gohda; Yuji Kobayashi; Ko Fujimori; Toshiharu Tsurumura; Kosuke Aritake; Yoshihiro Urade; Tadayasu Ohkubo JOURNAL OF BIOLOGICAL CHEMISTRY 283 (13) 8772 -8772 2008年03月
- 鶴村俊治; 有竹浩介; 入倉大祐; 吾郷日出夫; 島本茂; 大久保忠恭; 宮野雅司; 裏出良博 日本蛋白質科学会年会プログラム・要旨集 8th 2008年
- 島本茂; 圓尾廣子; 吉田卓也; 乾隆; 乾隆; 宮本優也; 小林祐次; 藤森功; 藤森功; 鶴村俊治; 有竹浩介; 裏出良博; 大久保忠恭 日本蛋白質科学会年会プログラム・要旨集 8th 2008年
- 有竹浩介; 島本茂; 鶴村俊治; 阪田真澄; 大久保忠恭; 裏出良博 日本蛋白質科学会年会プログラム・要旨集 8th 2008年
- 有竹浩介; 鶴村俊治; 阪田真澄; 島本茂; 大久保忠恭; 裏出良博 生化学 2008年
- 島本茂; 吉田卓也; 乾隆; 乾隆; 合田圭吾; 小林祐次; 藤森功; 有竹浩介; 裏出良博; 大久保忠恭 日本蛋白質科学会年会プログラム・要旨集 7th 2007年
書籍等出版物
担当経験のある科目_授業
共同研究・競争的資金等の研究課題
- 5-アミノレブリン酸の抗ウイルス効果におけるメカニズム解明研究ネオファーマジャパン株式会社:研究期間 : 2019年10月 -2021年03月代表者 : 島本 茂; 石川 知弘
- 日本学術振興会:科学研究費助成事業 基盤研究(A)研究期間 : 2016年04月 -2019年03月代表者 : 裏出 良博; 藤森 功; 相原 一; 供田 洋; 島本 茂プロスタグランジン(PG)D2を作るL型とH型の合成酵素、及び、その受容体DPとCRTH2に対する抗体や遺伝子操作マウスを作成して、睡眠や炎症における関与を調べた。脳のくも膜のL型酵素がPGD2を産生し、アデノシンを介して側坐核のA2A受容体発現神経を刺激して睡眠を起こすことを証明した。新生血管に発現するDP受容体が癌組織への血管新生を抑制することを見出した。高脂肪食により未成熟脂肪細胞でL型酵素が誘導され、CRTH2受容体を介して肥満の制御に関わることを見出した。治療法の無い難病であるデュシェンヌ型筋ジストロフィーの筋委縮に関わるH型酵素の阻害薬を開発して、臨床試験を開始した。
- 日本学術振興会:科学研究費助成事業 若手研究(B)研究期間 : 2016年04月 -2019年03月代表者 : 島本 茂リポカリン型プロスタグランジンD合成酵素(L-PGDS)は睡眠物質(PGD2)を合成する酵素であり、睡眠中枢を活性化することで哺乳類の睡眠導入や概日サイクル(体内時計)調節に関与している。従って、L-PGDSをターゲットとした創薬は新規作用機序を持つ睡眠調節薬の開発につながる。本研究では、L-PGDSの分子内部にある2つの基質結合部位の同定とさらにそれぞれの結合部位がどのようにプロスタグランジンの認識に関与するかを明らかにした。また、熱力学的パラメータの取得より、それぞれの結合部位の相互作用の特徴付けを行った。
- 日本学術振興会:科学研究費助成事業 基盤研究(C)研究期間 : 2012年04月 -2016年03月代表者 : 日高 雄二; 山口 宏; 島本 茂我々は、分子進化において、ペプチドホルモンの生理活性構造が如何に保たれ、高い生理活性を獲得したのかを前駆体の立体構造形成との関連から開明することを目的とし、プロウログアニリンあるいはその他の種々の前駆体について、立体構造形成反応を調査した。その結果、i)成熟ペプチドホルモンの生理活性は前駆体の立体構造形成反応レベルで品質管理が行われていること、ii)分子進化を促進する立体構造部位が存在すること、iii)分子進化を抑制する立体構造部位が存在すること、iv)天然型の立体構造と異なる反応中間体を経由することにより、より高度な品質管理機構を発展させたことを明らかにした。
- 日本学術振興会:科学研究費助成事業 若手研究(B)研究期間 : 2012年04月 -2014年03月代表者 : 島本 茂リポカリン型プロスタグランジンD合成酵素(L-PGDS)は、睡眠調節薬開発のターゲットとして多くの研究が為されてきたが、生成物(PGD2)の放出過程のメカニズムは明らかになっていない。本研究では、L-PGDSのPGD2認識・放出機構を熱力学的および構造生物学的に明らかにした。まず、従来考えられていたL-PGDSと基質/生成物の1:1相互作用モデルとは異なる、1:2結合モデルで相互作用することが明らかにした。また、活性中心のCys65が、生成物PGD2との相互作用にも非常に重要な役割を果たしていることが示された。さらに、得られた構造情報から基質の結合に重要な2つの領域を同定した。
- 日本学術振興会:科学研究費助成事業 特別研究員奨励費研究期間 : 2009年 -2010年代表者 : 島本 茂本研究は、脳内の主要蛋白質であるL-PGDSの機能を原子レベルで解明することで、生体内のL-PGDSをターゲットとした睡眠調節薬やL-PGDSを利用した疎水性有害物質除去薬(解毒剤)、または、アミロイドβ(Aβ)凝集阻害によるアルツハイマー病治療薬などの開発を目指す。 L-PGDSとPGH_2(基質)安定誘導体U-46619を結合させ、複合体が溶液中で安定な条件を模索し、NMR測定(約2週間)に十分耐えうる安定な溶液状態を決定後、NMRによりL-PGDS/U-46619複合体の溶液構造を解析した。結果として、L-PGDSは基質結合により構造変化を起こし、基質を厳密に固定することで酵素反応を可能にすることを明らかにした。得られた成果は、学会等で発表した。 また、アミロイド繊維形成過程における脳内シャペロンL-PGDSの役割解明のためL-PGDSとAβペプチドの相互作用解析を行った。具体的には、^<15>Nラベル体L-PGDSにAβペプチドを滴下し、それに伴うNMRシグナルの変化を見ることでL-PGDSにおけるAβペプチドの相互作用領域を推定した。L-PGDSがAβペプチドに結合すること、さらに、バレル構造を有するL-PGDSのバレル内部にAβペプチドが結合することが示唆された。
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