Structural and functional diversity among agonist-bound states of the GLP-1 receptor

Brian P Cary; Giuseppe Deganutti; Peishen Zhao; Tin T Truong; Sarah J Piper; Xinyu Liu; Matthew J Belousoff; Radostin Danev; Patrick M Sexton; Denise Wootten; Samuel H Gellman

doi:10.1038/s41589-021-00945-w

Structural and functional diversity among agonist-bound states of the GLP-1 receptor

Brian P Cary, Giuseppe Deganutti, Peishen Zhao, Tin T Truong, Sarah J Piper, Xinyu Liu, Matthew J Belousoff, Radostin Danev, Patrick M Sexton, Denise Wootten, Samuel H Gellman

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Abstract

Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and Gs heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.

Original language	English
Pages (from-to)	256-263
Number of pages	8
Journal	Nature Chemical Biology
Volume	18
Issue number	3
Early online date	22 Dec 2021
DOIs	https://doi.org/10.1038/s41589-021-00945-w
Publication status	Published - Mar 2022

Bibliographical note

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

Funder

This work was supported by the National Institutes of Health (R01 GM056414, to S.H.G.). B.P.C. was supported in part by a graduate fellowship from the NSF (DGE-1747503) and by a Biotechnology Training Grant from NIGMS (T32 GM008349). R.D. was supported by a Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). P.M.S. and D.W. were supported by an ARC Centre Grant (IC200100052). P.M.S. was supported by the National Health and Medical Research Council of Australia (NHMRC) Program Grant (1150083) and Senior Principal Research Fellowship (1154434). D.W. was supported by NHMRC Project Grants (1126857 and 1184726) and a NHMRC Senior Research Fellowship (1155302). This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grants P41GM136463 and P41RR002301; equipment was purchased with funds from the University of Wisconsin-Madison, the NIH (P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062, S10RR029220) and the NSF (DMB-8415048, OIA-9977486, BIR-9214394).

Funding

This work was supported by the National Institutes of Health (R01 GM056414, to S.H.G.). B.P.C. was supported in part by a graduate fellowship from the NSF (DGE-1747503) and by a Biotechnology Training Grant from NIGMS (T32 GM008349). R.D. was supported by a Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). P.M.S. and D.W. were supported by an ARC Centre Grant (IC200100052). P.M.S. was supported by the National Health and Medical Research Council of Australia (NHMRC) Program Grant (1150083) and Senior Principal Research Fellowship (1154434). D.W. was supported by NHMRC Project Grants (1126857 and 1184726) and a NHMRC Senior Research Fellowship (1155302). This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grants P41GM136463 and P41RR002301; equipment was purchased with funds from the University of Wisconsin-Madison, the NIH (P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062, S10RR029220) and the NSF (DMB-8415048, OIA-9977486, BIR-9214394).

Funders	Funder number
National Science Foundation	DGE-1747503, DMB-8415048, OIA-9977486, BIR-9214394
National Institutes of Health	P41RR002301, R01 GM056414, P41GM136463, S10RR025062, S10RR023438, S10RR08438, S10RR02781, S10RR029220
National Institute of General Medical Sciences	T32 GM008349, P41GM103399
University of Wisconsin- Madison
Takeda Science Foundation
Australian Research Council	IC200100052
National Health and Medical Research Council	1150083, 1184726, 1154434, 1155302, 1126857
Japan Science and Technology Agency	18069571

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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abstract = "Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their conformational mobility; however, the relationship between receptor function and static structures is inherently uncertain. Here, we examine the contribution of peptide agonist conformational plasticity to activation of the glucagon-like peptide 1 receptor (GLP-1R), an important clinical target. We use variants of the peptides GLP-1 and exendin-4 (Ex4) to explore the interplay between helical propensity near the agonist N terminus and the ability to bind to and activate the receptor. Cryo-EM analysis of a complex involving an Ex4 analog, the GLP-1R and Gs heterotrimer revealed two receptor conformers with distinct modes of peptide-receptor engagement. Our functional and structural data, along with molecular dynamics (MD) simulations, suggest that receptor conformational dynamics associated with flexibility of the peptide N-terminal activation domain may be a key determinant of agonist efficacy.",

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Structural and functional diversity among agonist-bound states of the GLP-1 receptor

Abstract

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