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

Liang, Yi-Lynn and Khoshouei, Maryam and Deganutti, Giuseppe and Glukhova, Alisa and Koole, Cassandra and Peat, Thomas S and Radjainia, Mazdak and Plitzko, Jürgen M and Baumeister, Wolfgang and Miller, Laurence J and Hay, Deborah L and Christopoulos, Arthur and Reynolds, Christopher A and Wootten, Denise and Sexton, Patrick M (2018) 'Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor.' Nature. ISSN 0028-0836

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Abstract

Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that plays 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 the type 1 transmembrane domain protein, receptor activity modifying protein (RAMP) 1. Herein, we report the 3.3 Å structure of the human CGRP receptor in complex with CGRP and the Gs40 protein heterotrimer determined by Volta phase plate cryo-electron microscopy. The RAMP transmembrane domain sits at the interface between transmembrane domains 3, 4 and 5 of CLR, and stabilises CLR extracellular loop 2. RAMP1 makes only limited direct interaction with CGRP, consistent with allosteric modulation of CLR as its key function. Molecular dynamics simulations indicate that RAMP1 provides stability to the receptor complex, particularly the location of the CLR extracellular domain. The work provides novel insight into the control of G-protein-coupled receptor function.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 13 Sep 2018 11:17
Last Modified: 13 Aug 2019 17:15
URI: http://repository.essex.ac.uk/id/eprint/22843

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