Biased GPCR signaling mechanism

2022 Fiscal Year Final Research Report

• 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
• Keywords: GPCR / 構造解析 / バイアス型

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.

Free Research Field

構造生物学

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。