Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes

Xin Zhang; Matthew J. Belousoff; Yi Lynn Liang; Radostin Danev; Patrick M. Sexton; Denise Wootten

doi:10.1016/j.celrep.2021.109374

Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes

Xin Zhang, Matthew J. Belousoff, Yi Lynn Liang, Radostin Danev, Patrick M. Sexton, Denise Wootten

Drug Discovery Biology

Research output: Contribution to journal › Article › Research › peer-review

37 Citations (Scopus)

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement.

Original language	English
Article number	109374
Number of pages	15
Journal	Cell Reports
Volume	36
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2021.109374
Publication status	Published - 13 Jul 2021

Keywords

cryoelectron microscopy
GLP-1R
glucagon-like peptide-1 receptor
GPCR dynamics
GPCRs
semaglutide
tasopglutide

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.109374Licence: CC BY

Cite this

@article{bb5491b6812c4011b8584c872691db88,

title = "Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes",

abstract = "The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement. ",

keywords = "cryoelectron microscopy, GLP-1R, glucagon-like peptide-1 receptor, GPCR dynamics, GPCRs, semaglutide, tasopglutide",

author = "Xin Zhang and Belousoff, {Matthew J.} and Liang, {Yi Lynn} and Radostin Danev and Sexton, {Patrick M.} and Denise Wootten",

note = "Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (project grant 1126857 , ideas grant 1184726 , and SRF 1160076 , to D.W., and program grant 1150083 , to P.M.S.). P.M.S. is a senior principal research fellow and D.W. is a senior research fellow of the NHMRC. R.D. was supported by the Takeda Science Foundation 2019 Medical Research Grant and the Japan Science and Technology Agency PRESTO ( 18069571 ). This work was supported by the Monash University MASSIVE high-performance computing facility . Publisher Copyright: {\textcopyright} 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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AU - Zhang, Xin

AU - Belousoff, Matthew J.

AU - Liang, Yi Lynn

AU - Danev, Radostin

AU - Sexton, Patrick M.

AU - Wootten, Denise

N1 - Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (project grant 1126857 , ideas grant 1184726 , and SRF 1160076 , to D.W., and program grant 1150083 , to P.M.S.). P.M.S. is a senior principal research fellow and D.W. is a senior research fellow of the NHMRC. R.D. was supported by the Takeda Science Foundation 2019 Medical Research Grant and the Japan Science and Technology Agency PRESTO ( 18069571 ). This work was supported by the Monash University MASSIVE high-performance computing facility . Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/7/13

Y1 - 2021/7/13

N2 - The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement.

AB - The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement.

KW - cryoelectron microscopy

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KW - GPCR dynamics

KW - GPCRs

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KW - tasopglutide

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JF - Cell Reports

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ER -

Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes

Abstract

Keywords

UN SDGs

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Other files and links

ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

Molecular control of efficacy at glucagon family of receptors

Translating membrane proteins into therapeutics; from bedside to bench

MASSIVE

Cite this

Structure and dynamics of semaglutide- and taspoglutide-bound GLP-1R-Gs complexes

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

Molecular control of efficacy at glucagon family of receptors

Translating membrane proteins into therapeutics; from bedside to bench

Equipment

MASSIVE

Cite this