Biased GPCR signaling mechanism

• Project/Area Number: 18H02388
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Shimamura Tatsuro 京都大学, 医学研究科, 特定准教授 (90391979)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: GPCR / 構造解析 / バイアス型 / 受容体 / Gタンパク質共役型受容体 / X線 / シグナル伝達

Outline of Final Research Achievements

Drugs that act on G protein-coupled receptors (GPCRs) often have side effects due to their poor selectivities of the receptor and the signaling pathway, etc. Aiming to understand the structural basis of these side　effects, we performed structural analysis of GPCRs in complex with several kinds of drugs. We succeeded to determine a structure of a GPCR bound with an inverse agonist, which was useful to understand the mechanism of the receptor selectivity of the drug. The structural studies for a GPCR in complex with several kinds of agonists are underway.

Academic Significance and Societal Importance of the Research Achievements

受容体や活性化経路の選択性に特徴のある薬剤とGPCRとの複合体の構造解析と構造比較により、薬剤の選択性に関する理解が深化する。本研究では主に、統合失調症などに関わるドパミンD2受容体（D2R）の構造解析を行った。D2Rにインバースアゴニストが結合した構造からは、受容体選択性の改善に利用可能と考えられる結合部位が見出された。各種アゴニストが結合した構造からは、活性化経路選択性に関する知見が取得できる。

Research Products

• [Journal Article] Structure and mechanism of oxalate transporter OxlT in an oxalate-degrading bacterium in the gut microbiota (2023)
  • Author(s): Jaunet-Lahary Titouan、Shimamura Tatsuro、Hayashi Masahiro、Nomura Norimichi、Hirasawa Kouta、Shimizu Tetsuya、Yamashita Masao、Tsutsumi Naotaka、Suehiro Yuta、Kojima Keiichi、Sudo Yuki、Tamura Takashi、Iwanari Hiroko、Hamakubo Takao、Iwata So、Okazaki Kei-ichi、Hirai Teruhisa、Yamashita Atsuko
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 1730-1730
  • DOI: 10.1038/s41467-023-36883-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] S1PR3?G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation (2021)
  • Author(s): Toyomoto Masayasu、Inoue Asuka、Iida Kei、Denawa Masatsugu、Kii Isao、Ngako Kadji Francois Marie、Kishi Takayuki、Im Dohyun、Shimamura Tatsuro、Onogi Hiroshi、Yoshida Suguru、Iwata So、Aoki Junken、Hosoya Takamitsu、Hagiwara Masatoshi
  • Journal Title: Cell Chemical Biology Volume: 未定 Issue: 8 Pages: 1132-1144
  • DOI: 10.1016/j.chembiol.2021.01.004
  • Peer Reviewed / Open Access
• [Journal Article] Time-resolved serial femtosecond crystallography reveals early structural changes in channelrhodopsin (2021)
  • Author(s): Oda Kazumasa、Nomura Takashi、Nakane Takanori、Yamashita Keitaro、Inoue Keiichi、Ito Shota、Vierock Johannes、Hirata Kunio、Maturana Andres D、Katayama Kota、( 32 authers )、Kandori Hideki、Hegemann Peter、Iwata So、Kubo Minoru、Nishizawa Tomohiro、Nureki Osamu
  • Journal Title: eLife Volume: 10 Pages: 1-21
  • DOI: 10.7554/elife.62389
  • NAID: 120006996980
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GPCRの構造解析研究 (2021)
  • Author(s): 島村達郎
  • Journal Title: 医学のあゆみ Volume: 278 Pages: 573-579
• [Journal Article] Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone (2020)
  • Author(s): Im Dohyun、Inoue Asuka、Fujiwara Takaaki、Nakane Takanori、Yamanaka Yasuaki、Uemura Tomoko、Mori Chihiro、Shiimura Yuki、Kimura Kanako Terakado、Asada Hidetsugu、Nomura Norimichi、Tanaka Tomoyuki、Yamashita Ayumi、Nango Eriko、Tono Kensuke、Kadji Francois Marie Ngako、Aoki Junken、Iwata So、Shimamura Tatsuro
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1-11
  • DOI: 10.1038/s41467-020-20221-0
  • NAID: 120006943309
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone (2020)
  • Author(s): Asada Hidetsugu、Inoue Asuka、Ngako Kadji Francois Marie、Hirata Kunio、Shiimura Yuki、Im Dohyun、Shimamura Tatsuro、Nomura Norimichi、Iwanari Hiroko、Hamakubo Takao、Kusano-Arai Osamu、Hisano Hiromi、Uemura Tomoko、Suno Chiyo、Aoki Junken、Iwata So
  • Journal Title: Structure Volume: 28 Issue: 4 Pages: 418-425.e4
  • DOI: 10.1016/j.str.2019.12.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High-viscosity sample-injection device for serial femtosecond crystallography at atmospheric pressure (2019)
  • Author(s): Shimazu Yoshiaki、Tono Kensuke、Tanaka Tomoyuki、Yamanaka Yasuaki、Nakane Takanori、Mori Chihiro、Terakado Kimura Kanako、Fujiwara Takaaki、Sugahara Michihiro、Tanaka Rie、Doak R. Bruce、Shimamura Tatsuro、Iwata So、Nango Eriko、Yabashi Makina
  • Journal Title: Journal of Applied Crystallography Volume: 52 Issue: 6 Pages: 1280-1288
  • DOI: 10.1107/s1600576719012846
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural basis for the substrate recognition of aminoglycoside 7′′-phosphotransferase-Ia from Streptomyces hygroscopicus (2019)
  • Author(s): Takenoya Mihoko、Shimamura Tatsuro、Yamanaka Ryuji、Adachi Yuya、Ito Shinsaku、Sasaki Yasuyuki、Nakamura Akira、Yajima Shunsuke
  • Journal Title: Acta Crystallographica Section F Structural Biology Communications Volume: 75 Issue: 9 Pages: 599-607
  • DOI: 10.1107/s2053230x19011105
  • NAID: 120007133009
  • Peer Reviewed / Open Access
• [Journal Article] Structures of the 5-HT2A receptor in complex with the antipsychotics risperidone and zotepine (2019)
  • Author(s): Kimura Kanako Terakado、Asada Hidetsugu、Inoue Asuka、Kadji Francois Marie Ngako、Im Dohyun、Mori Chihiro、Arakawa Takatoshi、Hirata Kunio、Nomura Yayoi、Nomura Norimichi、Aoki Junken、Iwata So、Shimamura Tatsuro
  • Journal Title: Nature Structural & Molecular Biology Volume: 26 Issue: 2 Pages: 121-128
  • DOI: 10.1038/s41594-018-0180-z
  • Peer Reviewed
• [Journal Article] Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog (2018)
  • Author(s): Asada H, Horita S, Hirata K, Shiroishi M, Shiimura Y, Iwanari H, Hamakubo T, Shimamura T, Nomura N, Kusano-Arai O, Uemura T, Suno C, Kobayashi T, Iwata S.
  • Journal Title: Nature Structural and Molecular Biology Volume: 25 Issue: 7 Pages: 570-576
  • DOI: 10.1038/s41594-018-0079-8
  • Peer Reviewed
• [Journal Article] Structure, Substrate Recognition, and Mechanism of the Na+-Hydantoin Membrane Transport Protein, Mhp1 (2018)
  • Author(s): Jackson Scott M.、Ivanova Ekaterina、Calabrese Antonio N.、Polyakova Anna、Sharples David J.、Shimamura Tatsuro、Cameron Alexander D.、Henderson Peter J. F., et al.
  • Journal Title: Encyclopedia of Biophysics Volume: 1 Pages: 1-12
  • DOI: 10.1007/978-3-642-35943-9_10091-1
  • ISBN: 9783642359439
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Structure of orexin receptor determined using X-ray free electron laser. (2018)
  • Author(s): Shimamura T.
  • Organizer: AsCA 2018/Crystal32
  • Int'l Joint Research / Invited
• [Book] 構造生命科学による創薬への挑戦 (2022)
  • Author(s): 岩崎憲治（編）、島村達郎ら
  • Total Pages: 146
  • Publisher: 医歯薬出版
• [Book] 創薬研究のための相互作用解析パーフェクト (2021)
  • Author(s): 津本浩平・前仲勝実（編）、島村達郎ら
  • Total Pages: 368
  • Publisher: 羊土社
  • ISBN: 9784758122566