Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor

Rachel M. Johnson; Xin Zhang; Sarah J. Piper; Theodore J. Nettleton; Teresa H. Vandekolk; Christopher J. Langmead; Radostin Danev; Patrick M. Sexton; Denise Wootten

doi:10.1016/j.bbrc.2021.09.016

Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor

Rachel M. Johnson, Xin Zhang, Sarah J. Piper, Theodore J. Nettleton, Teresa H. Vandekolk, Christopher J. Langmead, Radostin Danev, Patrick M. Sexton, Denise Wootten

Drug Discovery Biology

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

25 Citations (Scopus)

Abstract

Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors. In this study, we solved the structure of peptide-19 bound to the GLP-1R in complex with Gs protein, and compared the structure and dynamics of this complex to that of published structures of GLP-1R:Gs in complex with other receptor agonists. Unlike other peptide-bound receptor complexes, peptide-19:GLP-1R:Gs demonstrated a more open binding pocket where transmembrane domain (TM) 6, TM7 and the interconnecting extracellular loop 3 (ECL3) were located away from the peptide, with no interactions between peptide-19 and TM6/ECL3. Analysis of conformational variance of the complex revealed that peptide-19 was highly dynamic and underwent binding and unbinding motions facilitated by the more open TM binding pocket. Both the consensus structure of the GLP-1R complex with peptide-19 and the dynamics of this complex were distinct from previously described GLP-1R structures providing unique insights into the mode of GLP-1R activation by this dual agonist.

Original language	English
Pages (from-to)	84-90
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	578
DOIs	https://doi.org/10.1016/j.bbrc.2021.09.016
Publication status	Published - 12 Nov 2021

Keywords

Conformational dynamics
Cryo-EM
Dual agonist
GIPR
GLP-1R

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10.1016/j.bbrc.2021.09.016

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Johnson, R. M., Zhang, X., Piper, S. J., Nettleton, T. J., Vandekolk, T. H., Langmead, C. J., Danev, R., Sexton, P. M., & Wootten, D. (2021). Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor. Biochemical and Biophysical Research Communications, 578, 84-90. https://doi.org/10.1016/j.bbrc.2021.09.016

@article{0c3febee6995488ea1cf32a983dc086b,

title = "Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor",

abstract = "Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors. In this study, we solved the structure of peptide-19 bound to the GLP-1R in complex with Gs protein, and compared the structure and dynamics of this complex to that of published structures of GLP-1R:Gs in complex with other receptor agonists. Unlike other peptide-bound receptor complexes, peptide-19:GLP-1R:Gs demonstrated a more open binding pocket where transmembrane domain (TM) 6, TM7 and the interconnecting extracellular loop 3 (ECL3) were located away from the peptide, with no interactions between peptide-19 and TM6/ECL3. Analysis of conformational variance of the complex revealed that peptide-19 was highly dynamic and underwent binding and unbinding motions facilitated by the more open TM binding pocket. Both the consensus structure of the GLP-1R complex with peptide-19 and the dynamics of this complex were distinct from previously described GLP-1R structures providing unique insights into the mode of GLP-1R activation by this dual agonist.",

keywords = "Conformational dynamics, Cryo-EM, Dual agonist, GIPR, GLP-1R",

author = "Johnson, {Rachel M.} and Xin Zhang and Piper, {Sarah J.} and Nettleton, {Theodore J.} and Vandekolk, {Teresa H.} and Langmead, {Christopher J.} and Radostin Danev and Sexton, {Patrick M.} and Denise Wootten",

note = "Funding Information: The authors thank Dr. Matthew Belousoff for helpful discussions. Molecular graphics and analyses were performed with Pymol (Version 2.5.1, Schrodinger, LLC) and UCSF ChimeraX (Version 1.2.5; Resource for Biocomputing, Visualization, and Informatics, UCSF), with support from NIH R01-GM129325. The work was supported by the Monash MASSIVE high-performance computing facility. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = nov,

day = "12",

doi = "10.1016/j.bbrc.2021.09.016",

language = "English",

volume = "578",

pages = "84--90",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Elsevier",

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TY - JOUR

T1 - Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor

AU - Johnson, Rachel M.

AU - Zhang, Xin

AU - Piper, Sarah J.

AU - Nettleton, Theodore J.

AU - Vandekolk, Teresa H.

AU - Langmead, Christopher J.

AU - Danev, Radostin

AU - Sexton, Patrick M.

AU - Wootten, Denise

N1 - Funding Information: The authors thank Dr. Matthew Belousoff for helpful discussions. Molecular graphics and analyses were performed with Pymol (Version 2.5.1, Schrodinger, LLC) and UCSF ChimeraX (Version 1.2.5; Resource for Biocomputing, Visualization, and Informatics, UCSF), with support from NIH R01-GM129325. The work was supported by the Monash MASSIVE high-performance computing facility. Publisher Copyright: © 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/11/12

Y1 - 2021/11/12

N2 - Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors. In this study, we solved the structure of peptide-19 bound to the GLP-1R in complex with Gs protein, and compared the structure and dynamics of this complex to that of published structures of GLP-1R:Gs in complex with other receptor agonists. Unlike other peptide-bound receptor complexes, peptide-19:GLP-1R:Gs demonstrated a more open binding pocket where transmembrane domain (TM) 6, TM7 and the interconnecting extracellular loop 3 (ECL3) were located away from the peptide, with no interactions between peptide-19 and TM6/ECL3. Analysis of conformational variance of the complex revealed that peptide-19 was highly dynamic and underwent binding and unbinding motions facilitated by the more open TM binding pocket. Both the consensus structure of the GLP-1R complex with peptide-19 and the dynamics of this complex were distinct from previously described GLP-1R structures providing unique insights into the mode of GLP-1R activation by this dual agonist.

AB - Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors. In this study, we solved the structure of peptide-19 bound to the GLP-1R in complex with Gs protein, and compared the structure and dynamics of this complex to that of published structures of GLP-1R:Gs in complex with other receptor agonists. Unlike other peptide-bound receptor complexes, peptide-19:GLP-1R:Gs demonstrated a more open binding pocket where transmembrane domain (TM) 6, TM7 and the interconnecting extracellular loop 3 (ECL3) were located away from the peptide, with no interactions between peptide-19 and TM6/ECL3. Analysis of conformational variance of the complex revealed that peptide-19 was highly dynamic and underwent binding and unbinding motions facilitated by the more open TM binding pocket. Both the consensus structure of the GLP-1R complex with peptide-19 and the dynamics of this complex were distinct from previously described GLP-1R structures providing unique insights into the mode of GLP-1R activation by this dual agonist.

KW - Conformational dynamics

KW - Cryo-EM

KW - Dual agonist

KW - GIPR

KW - GLP-1R

UR - http://www.scopus.com/inward/record.url?scp=85115079489&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2021.09.016

DO - 10.1016/j.bbrc.2021.09.016

M3 - Article

AN - SCOPUS:85115079489

SN - 0006-291X

VL - 578

SP - 84

EP - 90

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

ER -

Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor

Abstract

Keywords

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

Cite this

Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor

Abstract

Keywords

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

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