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; Jürgen M. Plitzko; Wolfgang Baumeister; Laurence J. Miller; Deborah L. Hay; Arthur Christopoulos; Christopher A. Reynolds; Denise Wootten; Patrick M. Sexton

doi:10.1038/s41586-018-0535-y

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, 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 journal › Article › peer-review

203 Citations (Scopus)

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 _s -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 language	English
Pages (from-to)	492-497
Number of pages	6
Journal	Nature
Volume	561
Issue number	7724
DOIs	https://doi.org/10.1038/s41586-018-0535-y
Publication status	Published - 12 Sept 2018
Externally published	Yes

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.

Keywords

Calcitonin Gene-related Peptide (CGRP)
CGRP Receptor
Receptor Activity-modifying Proteins (RAMP1)
Lauryl Maltose Neopentyl Glycol (LMNG)
Receptor Core

ASJC Scopus subject areas

General

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10.1038/s41586-018-0535-y

Cite this

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. (2018). Cryo-EM structure of the active, G _s -protein complexed, human CGRP receptor. Nature, 561(7724), 492-497. https://doi.org/10.1038/s41586-018-0535-y

Liang, YL, 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, G _s -protein complexed, human CGRP receptor', Nature, vol. 561, no. 7724, pp. 492-497. https://doi.org/10.1038/s41586-018-0535-y

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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 G s -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. ",

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AU - Hay, Deborah L.

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

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Keywords

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Giuseppe Deganutti

Chris Reynolds

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

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ASJC Scopus subject areas

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Giuseppe Deganutti

Chris Reynolds

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