Journal article
Structure and dynamics of the active Gs-coupled human secretin receptor
M Dong, G Deganutti, SJ Piper, YL Liang, M Khoshouei, MJ Belousoff, KG Harikumar, CA Reynolds, A Glukhova, SGB Furness, A Christopoulos, R Danev, D Wootten, PM Sexton, LJ Miller
Nature Communications | NATURE PORTFOLIO | Published : 2020
Abstract
The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (E..
View full abstractRelated Projects (1)
Grants
Awarded by Takeda Science Foundation
Funding Acknowledgements
The work was supported by a grant from the National Institutes of Health, GM-132095 (L.J.M. and P.M.S.), the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, the Monash MASSIVE high-performance computing facility, the National Health and Medical Research Council of Australia (NHMRC) project grant (1120919), and NHMRC program grant (1150083). P.M.S. and A.C. are NHMRC Senior Principal Research Fellows and D.W. is an NHMRC Senior Research Fellow. C.A.R. holds a Royal Society Industry Fellowship and acknowledges a grant from the United Kingdom Biotechnology and Biological Sciences Research Council (BB/M006883/1). R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571).