Journal article
Cryo-EM structure of the active, G s -protein complexed, human CGRP receptor
YL Liang, M Khoshouei, G Deganutti, A Glukhova, C Koole, TS Peat, M Radjainia, JM Plitzko, W Baumeister, LJ Miller, DL Hay, A Christopoulos, CA Reynolds, D Wootten, PM Sexton
Nature | NATURE PUBLISHING GROUP | Published : 2018
Abstract
Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) class B G-protein-coupled receptor and a type 1 transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Here we report the structure of the human CGRP receptor in complex with CGRP and the G s -protein heterotrimer at 3.3 Å global resolution, determined by Volta phase-plate cryo-electron microscopy. The receptor activity-modifying protein transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilizes CLR extracellular loop ..
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Awarded by Australian Research Council
Funding Acknowledgements
The work was supported by the Monash University Ramaciotti Centre for Cryo-Electron Microscopy, National Health and Medical Research Council of Australia (NHMRC) project grant (1120919), and NHMRC program grant (1055134). P.M.S. and A.C. are NHMRC Principal and Senior Principal Research Fellows, respectively. D.W. is a NHMRC Career Development Fellow, and C.K. is a NHMRC CJ Martin Fellow. A.G. is an Australian Research Council DECRA Fellow. D.L.H. is a James Cook Research Fellow and is supported by the Marsden Fund (both Royal Society of New Zealand). C.A.R. is a Royal Society Industry Fellow and acknowledges support from the BBSRC (BB/M006883/1). We are grateful to G. Christopoulos and V. Julita for assay and technical support, T. Coudrat for initial homology modelling of CLR from the active CTR, and to S. Furness, P. Zhao and D. Thal for useful discussion.