Structural study for ligand recognition in G-protein coupled receptors

• Project/Area Number: 17H05000
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Functional biochemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Nishizawa Tomohiro 東京大学, 大学院理学系研究科(理学部), 助教 (80599077)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥26,260,000 (Direct Cost: ¥20,200,000、Indirect Cost: ¥6,060,000); Fiscal Year 2019: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2018: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2017: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
• Keywords: GPCR / X線結晶構造解析 / クライオ電子顕微鏡 / 構造生物学 / Gタンパク質共役型受容体 / 膜タンパク質 / 結晶構造解析 / Gタンパク質共役受容体 / 生物物理

Outline of Final Research Achievements

We revealed the structural basis for the ligand recognition and activation of G-protein coupled receptors (GPCRs), by solving the structures of various receptors. In this research, we have successfully obtained the structures of endothelin reeptor subtype-B (ETB), non-EDG LPA receptor LPA6, and pituitary adenylate cyclase-activating polypeptid (PACAP) receptor, and the structural comparison revealed similarity and diversity of GPCRs.

Academic Significance and Societal Importance of the Research Achievements

Gタンパク質共役型受容体（GPCR）はヒトを含む真核生物において細胞間でのシグナル伝達に関わる重要な膜タンパク質ファミリーである。既存の承認薬の30%はGPCRを標的するのに対して、いまだに構造の明らかになっていない受容体の数は多い。本研究では、血圧調節に関わるペプチド受容体であるエンドセリン受容体、細胞増殖などに関わる脂質受容体であるLPA6、神経における重要なシグナル伝達分子である下垂体アデニル酸シクラーゼ活性化ポリペプチド（PACAP）の受容体などに関して、構造を明らかにした。これらの情報は、構造をもとにした薬剤開発などにつながることが期待される。

Research Products

• [Journal Article] Cryo-EM structure of the human PAC1 receptor coupled to an engineered heterotrimeric G protein (2020)
  • Author(s): Kobayashi Kazuhiro、Shihoya Wataru、Nishizawa Tomohiro、Kadji Francois Marie Ngako、Aoki Junken、Inoue Asuka、Nureki Osamu
  • Journal Title: Nature Structural & Molecular Biology Volume: 27 Pages: 274-280
  • DOI: 10.1038/s41594-020-0386-8
  • Peer Reviewed / Open Access
• [Journal Article] Crystal structures of human ETB receptor provide mechanistic insight into receptor activation and partial activation (2018)
  • Author(s): Shihoya Wataru、Izume Tamaki、Inoue Asuka、Yamashita Keitaro、Kadji Francois Marie Ngako、Hirata Kunio、Aoki Junken、Nishizawa Tomohiro、Nureki Osamu
  • Journal Title: Nature Communications Volume: 9 Pages: 1-11
  • DOI: 10.1038/s41467-018-07094-0
  • Peer Reviewed / Open Access
• [Journal Article] X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog (2017)
  • Author(s): Shihoya Wataru、Nishizawa Tomohiro、Yamashita Keitaro、Inoue Asuka、Hirata Kunio、Kadji Francois Marie Ngako、Okuta Akiko、Tani Kazutoshi、Aoki Junken、Fujiyoshi Yoshinori、Doi Tomoko、Nureki Osamu
  • Journal Title: Nat. Struct. Mol. Biol Volume: 24 Pages: 758-764
  • DOI: 10.1038/nsmb.3450
  • Peer Reviewed
• [Journal Article] Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6 (2017)
  • Author(s): Taniguchi Reiya、Inoue Asuka、Sayama Misa、Uwamizu Akiharu、Yamashita Keitaro、Hirata Kunio、Yoshida Masahito、Tanaka Yoshiki、Kato Hideaki E.、Nakada-Nakura Yoshiko、Otani Yuko、Nishizawa Tomohiro、Doi Takayuki、Ohwada Tomohiko、Ishitani Ryuichiro、Aoki Junken、Nureki Osamu
  • Journal Title: Nature Volume: 548 Pages: 356-360
  • DOI: 10.1038/nature23448
  • Peer Reviewed / Open Access
• [Journal Article] Structure of the triose-phosphate/phosphate translocator reveals the basis of substrate specificity. (2017)
  • Author(s): Lee Y, Nishizawa T, Takemoto M, Kumazaki K, Yamashita K, Hirata K, Minoda A, Nagatoishi S, Tsumoto K, Ishitani R and Nureki O.
  • Journal Title: Nat. Plants. Volume: 3 Pages: 825-832
  • DOI: 10.1038/s41477-017-0022-8
  • Peer Reviewed / Open Access
• [Journal Article] Structural basis for xenobiotics extrusion by eukaryotic MATE transporter. (2017)
  • Author(s): Miyauchi H., Moriyama S., Kusakizako T., Kumazaki K., Ito K., Dohmae N., Nishizawa T., Miyaji T., Moriyama Y., Ishitani R., Nureki O.
  • Journal Title: Nat. Commun. Volume: 8 Pages: 1-11
  • DOI: 10.1038/s41467-017-01541-0
  • Peer Reviewed / Open Access
• [Presentation] Structural biology of membrane transporters (2019)
  • Author(s): Tomohiro Nishizawa
  • Organizer: Joint Annual Meeting of 71st JSCB & 19th PSSJ
  • Int'l Joint Research / Invited
• [Presentation] Membrane Transporter DynamicsRevealed by CryoEM (2019)
  • Author(s): Tomohiro Nishizawa
  • Organizer: The 92nd Annual Meeting of The Japanese Biochemical Society
  • Invited
• [Presentation] Structural Insights Into Tetraspanin Function (2019)
  • Author(s): Tomohiro Nishizawa
  • Organizer: Cold Spring Harbor Asia Conference CROSS-SCALE BIOLOGICAL STRUCTURE: FROM MACROMOLECULAR COMPLEXES & ORGANELLES TO CELLS & TISSUES
• [Presentation] X-ray crystal structures of the human endothelin type-B receptor (ETB) (2017)
  • Author(s): Tomohiro Nishizawa
  • Organizer: 15th Chinese Biophysics Congress (2017 ICBC)
  • Int'l Joint Research / Invited
• [Presentation] X線自由電子レーザーによって見えてきたチャネルロドプシンのイオン透過機構 (2017)
  • Author(s): 西澤知宏
  • Organizer: 第40回分子生物学会（ConBio 2017 ）
  • Invited
• [Remarks]
  • URL: https://www.s.u-tokyo.ac.jp/ja/press/2020/6729/