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

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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)492-497
Number of pages6
JournalNature
Volume561
Issue number7724
DOIs
Publication statusPublished - 27 Sep 2018

Cite this

Liang, Yi-Lynn ; Khoshouei, Maryam ; Deganutti, Giuseppe ; Glukhova, Alisa ; Koole, Cassandra ; Peat, Thomas S. ; Radjainia, Mazdak ; Plitzko, Jürgen M. ; Baumeister, Wolfgang ; Miller, Laurence J. ; Hay, Deborah L. ; Christopoulos, Arthur ; Reynolds, Christopher A. ; Wootten, Denise ; Sexton, Patrick M. / Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. In: Nature. 2018 ; Vol. 561, No. 7724. pp. 492-497.
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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 {\AA} 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.",
author = "Yi-Lynn Liang and Maryam Khoshouei and Giuseppe Deganutti and Alisa Glukhova and Cassandra Koole and Peat, {Thomas S.} and Mazdak Radjainia and Plitzko, {J{\"u}rgen M.} and Wolfgang Baumeister and Miller, {Laurence J.} and Hay, {Deborah L.} and Arthur Christopoulos and Reynolds, {Christopher A.} and Denise Wootten and Sexton, {Patrick M.}",
year = "2018",
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doi = "10.1038/s41586-018-0535-y",
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Liang, Y-L, Khoshouei, M, Deganutti, G, Glukhova, A, Koole, C, Peat, TS, Radjainia, M, Plitzko, JM, Baumeister, W, Miller, LJ, Hay, DL, Christopoulos, A, Reynolds, CA, Wootten, D & Sexton, PM 2018, 'Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor', Nature, vol. 561, no. 7724, pp. 492-497. https://doi.org/10.1038/s41586-018-0535-y

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

In: Nature, Vol. 561, No. 7724, 27.09.2018, p. 492-497.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor

AU - Liang, Yi-Lynn

AU - Khoshouei, Maryam

AU - Deganutti, Giuseppe

AU - Glukhova, Alisa

AU - Koole, Cassandra

AU - Peat, Thomas S.

AU - Radjainia, Mazdak

AU - Plitzko, Jürgen M.

AU - Baumeister, Wolfgang

AU - Miller, Laurence J.

AU - Hay, Deborah L.

AU - Christopoulos, Arthur

AU - Reynolds, Christopher A.

AU - Wootten, Denise

AU - Sexton, Patrick M.

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Y1 - 2018/9/27

N2 - 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.

AB - 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.

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DO - 10.1038/s41586-018-0535-y

M3 - Article

VL - 561

SP - 492

EP - 497

JO - Nature

JF - Nature

SN - 0028-0836

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