Structural basis of biased signaling mediated by pharmacologically important GPCRs

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K18843
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: KOFUKU Yutaka 東京大学, 大学院薬学系研究科(薬学部), 特任助教 (80737940)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 構造生物学 / NMR / 膜タンパク質 / シグナル伝達 / GPCR

Outline of Final Research Achievements

G-protein-coupled receptor (GPCR) ligands impart differing degrees of signaling in the G-protein and arrestin pathways, in phenomena called "biased signaling". However, the mechanism underlying the biased signaling of GPCRs is still unclear, although crystal structures of GPCRs bound to the G protein or arrestin are available. In this study, we observed the NMR signals from methionine residues of pharmacologically important GPCRs in the balanced- and biased-ligand-bound states. We found that the intracellular cavity of GPCRs exist in an equilibrium between closed and multiple open conformations, and that the population of each open conformation determines the G-protein- and arrestin-mediated signaling levels in each ligand-bound state.

Free Research Field

構造生物学