6E3Y

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

Summary for 6E3Y

• Entry DOI: 10.2210/pdb6e3y/pdb
• EMDB information: 8978
• Descriptor: Calcitonin gene-related peptide 1, Nanobody 35, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (7 entities in total)
• Functional Keywords: class b g protein-coupled receptor, agonist-receptor-g protein ternary complex, calcitonin gene-related peptide receptor, receptor activity modifying protein 1, active-state g protein-coupled receptor, signaling protein, phase plate, phase contrast
• Biological source: Lama glama (llama); More
• Total number of polymer chains: 7
• Total formula weight: 184355.96

Authors

Liang, Y.L.,Khoshouei, M.,Deganutti, G.,Glukhova, A.,Koole, C.,Peat, T.S.,Radjainia, M.,Plitzko, J.M.,Baumeister, W.,Miller, L.J.,Hay, D.L.,Christopoulos, A.,Reynolds, C.A.,Wootten, D.,Sexton, P.M. (deposition date: 2018-07-16, release date: 2018-09-19, Last modification date: 2024-11-13)

Primary citation

Liang, Y.L.,Khoshouei, M.,Deganutti, G.,Glukhova, A.,Koole, C.,Peat, T.S.,Radjainia, M.,Plitzko, J.M.,Baumeister, W.,Miller, L.J.,Hay, D.L.,Christopoulos, A.,Reynolds, C.A.,Wootten, D.,Sexton, P.M.
Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor.
Nature, 561:492-497, 2018

PubMed 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-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.

PubMed: 30209400
DOI: 10.1038/s41586-018-0535-y

Experimental method

ELECTRON MICROSCOPY (3.3 Å)