九州大学 研究者情報
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基本情報 研究活動 教育活動 社会活動
森本 和志(もりもと かずし) データ更新日:2021.09.16



主な研究テーマ
プロスタグランジン受容体の立体構造解析
キーワード:プロスタグランジン, GPCR, X線結晶構造解析
2014.01~2021.03.
研究業績
主要原著論文
1. Kazushi Morimoto, Ryoji Suno, Yunhong Hotta, Keitaro Yamashita, Kunio Hirata, Masaki Yamamoto, Shuh Narumiya, So Iwata, Takuya Kobayashi, Crystal structure of the endogenous agonist-bound prostanoid receptor EP3., Nature chemical biology, 10.1038/s41589-018-0171-8, 15, 1, 8-10, 2019.01, Prostanoids are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate G-protein-coupled receptors (GPCRs). Here, we report the crystal structure of human prostaglandin (PG) E receptor subtype EP3 bound to endogenous ligand PGE2 at 2.90 Å resolution. The structure reveals important insights into the activation mechanism of prostanoid receptors and provides a molecular basis for the binding modes of endogenous ligands..
2. Yosuke Toyoda, Kazushi Morimoto, Ryoji Suno, Shoichiro Horita, Keitaro Yamashita, Kunio Hirata, Yusuke Sekiguchi, Satoshi Yasuda, Mitsunori Shiroishi, Tomoko Shimizu, Yuji Urushibata, Yuta Kajiwara, Tomoaki Inazumi, Yunhon Hotta, Hidetsugu Asada, Takanori Nakane, Yuki Shiimura, Tomoya Nakagita, Kyoshiro Tsuge, Suguru Yoshida, Tomoko Kuribara, Takamitsu Hosoya, Yukihiko Sugimoto, Norimichi Nomura, Miwa Sato, Takatsugu Hirokawa, Masahiro Kinoshita, Takeshi Murata, Kiyoshi Takayama, Masaki Yamamoto, Shuh Narumiya, So Iwata, Takuya Kobayashi, Ligand binding to human prostaglandin E receptor EP4 at the lipid-bilayer interface., Nature chemical biology, 10.1038/s41589-018-0131-3, 15, 1, 18-26, 2019.01, Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. Functional and docking studies demonstrate that the natural agonist PGE2 binds in a similar manner. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. Furthermore, the structure reveals that the antibody allosterically affects the ligand binding of EP4. These results should facilitate the design of new therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family..
3. Kazushi Morimoto, Naritoshi Shirata, Yoshitaka Taketomi, Soken Tsuchiya, Eri Segi-Nishida, Tomoaki Inazumi, Kenji Kabashima, Satoshi Tanaka, Makoto Murakami, Shuh Narumiya, Yukihiko Sugimoto, Prostaglandin E-2-EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation, JOURNAL OF IMMUNOLOGY, 10.4049/jimmunol.1300290, 192, 3, 1130-1137, 2014.02, PGE(2) has long been known as a potentiator of acute inflammation, but its mechanisms of action still remain to be defined. In this study, we employed inflammatory swelling induced in mice by arachidonate and PGE(2) as models and dissected the role and mechanisms of action of each EP receptor at the molecular level. Arachidonate- or PGE(2)-induced vascular permeability was significantly reduced in EP3-deficient mice. Intriguingly, the PGE(2)-induced response was suppressed by histamine H-1 antagonist treatment, histidine decarboxylase deficiency, and mast cell deficiency. The impaired PGE(2)-induced response in mast cell-deficient mice was rescued upon reconstitution with wild-type mast cells but not with EP3-deficient mast cells. Although the number of mast cells, protease activity, and histamine contents in ear tissues in EP3-deficient mice were comparable to those in wild-type mice, the histamine contents in ear tissues were attenuated upon PGE(2) treatment in wild-type but not in EP3-deficient mice. Consistently, PGE(2)-EP3 signaling elicited histamine release in mouse peritoneal and bone marrow-derived mast cells, and it exerted degranulation and IL-6 production in a manner sensitive to pertussis toxin and a PI3K inhibitor and dependent on extracellular Ca2+ ions. These results demonstrate that PGE(2) triggers mast cell activation via an EP3-G(i/o)-Ca2+ influx/PI3K pathway, and this mechanism underlies PGE(2)-induced vascular permeability and consequent edema formation..
主要総説, 論評, 解説, 書評, 報告書等
主要学会発表等
学会活動
所属学会名
日本蛋白質科学会
日本薬学会
日本生化学会
受賞
奨励賞, 日本薬学会関西支部, 2020.01.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2020年度~2023年度, 基盤研究(B), プロスタグランジン受容体を標的とした構造に基づく創薬.
2015年度~2017年度, 特別研究員奨励費, 構造情報に基づく脂質シグナル分子の認識機構の解明.
2010年度~2012年度, 特別研究員奨励費, プロスタグランジン受容体による細胞特異的シグナリングの分子機構.

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