Format

Send to

Choose Destination
Nature. 2018 Sep;561(7724):492-497. doi: 10.1038/s41586-018-0535-y. Epub 2018 Sep 12.

Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor.

Author information

1
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
2
Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
3
Novartis Institutes for Biomedical Research, Novartis Pharma, Basel, Switzerland.
4
School of Biological Sciences, University of Essex, Colchester, UK.
5
CSIRO Biomedical Manufacturing, Melbourne, Victoria, Australia.
6
Thermo Fisher Scientific, Eindhoven, The Netherlands.
7
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, AZ, USA.
8
School of Biological Sciences, University of Auckland, Auckland, New Zealand.
9
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
10
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. denise.wootten@monash.edu.
11
School of Pharmacy, Fudan University, Shanghai, China. denise.wootten@monash.edu.
12
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia. patrick.sexton@monash.edu.
13
School of Pharmacy, Fudan University, Shanghai, China. patrick.sexton@monash.edu.

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. RAMP1 makes only limited direct contact with CGRP, consistent with its function in allosteric modulation of CLR. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly in the positioning of the extracellular domain of CLR. This work provides insights into the control of G-protein-coupled receptor function.

PMID:
30209400
PMCID:
PMC6166790
DOI:
10.1038/s41586-018-0535-y
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center