Journal article

Cryo-EM structure of the active, G(s)- protein complexed, human CGRP receptor

Yi-Lynn Liang, Maryam Khoshouei, Giuseppe Deganutti, Alisa Glukhova, Cassandra Koole, Thomas S Peat, Mazdak Radjainia, Jurgen M Plitzko, Wolfgang Baumeister, Laurence J Miller, Deborah L Hay, Arthur Christopoulos, Christopher A Reynolds, Denise Wootten, Patrick M 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 Gs-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 2...

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Grants

Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by NHMRC


Awarded by BBSRC


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.