Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists

Xin Zhang; Matthew J. Belousoff; Peishen Zhao; Albert J. Kooistra; Tin T. Truong; Sheng Yu Ang; Christina Rye Underwood; Thomas Egebjerg; Petr Šenel; Gregory D. Stewart; Yi Lynn Liang; Alisa Glukhova; Hari Venugopal; Arthur Christopoulos; Sebastian G.B. Furness; Laurence J. Miller; Steffen Reedtz-Runge; Christopher J. Langmead; David E. Gloriam; Radostin Danev; Patrick M. Sexton; Denise Wootten

doi:10.1016/j.molcel.2020.09.020

Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists

Xin Zhang, Matthew J. Belousoff, Peishen Zhao, Albert J. Kooistra, Tin T. Truong, Sheng Yu Ang, Christina Rye Underwood, Thomas Egebjerg, Petr Šenel, Gregory D. Stewart, Yi Lynn Liang, Alisa Glukhova, Hari Venugopal, Arthur Christopoulos, Sebastian G.B. Furness, Laurence J. Miller, Steffen Reedtz-Runge, Christopher J. Langmead, David E. Gloriam, Radostin DanevPatrick M. Sexton, Denise Wootten

Gastroenterology and Hepatology

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

12 Scopus citations

Abstract

Zhang et al. show that the non-peptide GLP-1R agonist PF 06882961, but not CHU-128, was able to closely mimic the in vitro pharmacological fingerprint of GLP-1. These pharmacological activities could be rationalized from high-resolution structures that provide a novel template for the design of new agonists targeting the GLP-1R.

Original language	English (US)
Pages (from-to)	485-500.e7
Journal	Molecular Cell
Volume	80
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2020.09.020
State	Published - Nov 5 2020

Keywords

G-protein-coupled receptor
GLP-1
cryoelectron microscopy
glucagon-like peptide-1 receptor
non-peptide agonists

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.09.020

Cite this

Zhang, X., Belousoff, M. J., Zhao, P., Kooistra, A. J., Truong, T. T., Ang, S. Y., Underwood, C. R., Egebjerg, T., Šenel, P., Stewart, G. D., Liang, Y. L., Glukhova, A., Venugopal, H., Christopoulos, A., Furness, S. G. B., Miller, L. J., Reedtz-Runge, S., Langmead, C. J., Gloriam, D. E., ... Wootten, D. (2020). Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. Molecular Cell, 80(3), 485-500.e7. https://doi.org/10.1016/j.molcel.2020.09.020

Zhang, X, Belousoff, MJ, Zhao, P, Kooistra, AJ, Truong, TT, Ang, SY, Underwood, CR, Egebjerg, T, Šenel, P, Stewart, GD, Liang, YL, Glukhova, A, Venugopal, H, Christopoulos, A, Furness, SGB, Miller, LJ, Reedtz-Runge, S, Langmead, CJ, Gloriam, DE, Danev, R, Sexton, PM & Wootten, D 2020, 'Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists', Molecular Cell, vol. 80, no. 3, pp. 485-500.e7. https://doi.org/10.1016/j.molcel.2020.09.020

@article{4abeb9cb63bf46b5b2f89e9db86310e9,

title = "Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists",

abstract = "Zhang et al. show that the non-peptide GLP-1R agonist PF 06882961, but not CHU-128, was able to closely mimic the in vitro pharmacological fingerprint of GLP-1. These pharmacological activities could be rationalized from high-resolution structures that provide a novel template for the design of new agonists targeting the GLP-1R.",

keywords = "G-protein-coupled receptor, GLP-1, cryoelectron microscopy, glucagon-like peptide-1 receptor, non-peptide agonists",

author = "Xin Zhang and Belousoff, {Matthew J.} and Peishen Zhao and Kooistra, {Albert J.} and Truong, {Tin T.} and Ang, {Sheng Yu} and Underwood, {Christina Rye} and Thomas Egebjerg and Petr {\v S}enel and Stewart, {Gregory D.} and Liang, {Yi Lynn} and Alisa Glukhova and Hari Venugopal and Arthur Christopoulos and Furness, {Sebastian G.B.} and Miller, {Laurence J.} and Steffen Reedtz-Runge and Langmead, {Christopher J.} and Gloriam, {David E.} 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) (nos. 1126857, 1184726, 1160076, and 1150083). P.M.S. is a Senior Principal Research Fellow and D.W. a Senior Research Fellow of the NHMRC. R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). D.E.G. was funded by the Lundbeck Foundation (R163-2013-16327) and A.J.K. from the Independent Research Fund Denmark (8021-00173B). This work was partially supported by the Monash University Ramaciotti Centre for cryoelectron microscopy and the Monash University MASSIVE high-performance computing facility. D.W. and P.M.S. conceived and formulated the research. X.Z. expressed and purified complexes; R.D. M.J.B. and H.V. performed sample vitrification and cryo-EM imaging; X.Z. M.J.B. and R.D. processed the EM data; X.Z. and M.J.B. generated atomic models; and X.Z. P.Z. T.T.T. S.Y.A. G.D.S. C.R.U. and T.E. generated DNA constructs and performed pharmacological assays. D.W. P.M.S. A.J.K. D.E.G. X.Z. and M.J.B. analyzed the receptor structures; D.W. X.Z. P.Z. C.R.U. and S.R.-R. analyzed pharmacological data. S.G.B.F. generated FLAG resin; P.{\v S}. synthesized CHU-128. D.W. and P.M.S. supervised the project; A.G. and Y.-L.L. assisted complex biochemistry supervision; and P.Z. S.R.-R. and C.J.L. supervised pharmacological experiments. Project administration was provided by D.W. P.M.S. R.D. and S.R.-R. D.W. X.Z. M.J.B. A.J.K. R.D. and P.M.S. prepared figures and videos. D.W. P.M.S. X.Z. A.J.K. and D.E.G. wrote the manuscript draft. M.J.B. P.Z. T.T.T. S.Y.A. C.R.U. A.C. S.G.B.F. L.J.M. S.R.-R. C.J.L. and R.D. reviewed and edited the manuscript. D.W. P.M.S. R.D. and D.E.G. acquired the financial support for the project. C.R.U. T.E. and S.R.-R. are employees of Novo Nordisk. P.{\v S}. is an employee of Apigenex. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (nos. 1126857 , 1184726 , 1160076 , and 1150083 ). P.M.S. is a Senior Principal Research Fellow and D.W. a Senior Research Fellow of the NHMRC. R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO ( 18069571 ). D.E.G. was funded by the Lundbeck Foundation ( R163-2013-16327 ) and A.J.K. from the Independent Research Fund Denmark ( 8021-00173B ). This work was partially supported by the Monash University Ramaciotti Centre for cryoelectron microscopy and the Monash University MASSIVE high-performance computing facility. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = nov,

day = "5",

doi = "10.1016/j.molcel.2020.09.020",

language = "English (US)",

volume = "80",

pages = "485--500.e7",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists

AU - Zhang, Xin

AU - Belousoff, Matthew J.

AU - Zhao, Peishen

AU - Kooistra, Albert J.

AU - Truong, Tin T.

AU - Ang, Sheng Yu

AU - Underwood, Christina Rye

AU - Egebjerg, Thomas

AU - Šenel, Petr

AU - Stewart, Gregory D.

AU - Liang, Yi Lynn

AU - Glukhova, Alisa

AU - Venugopal, Hari

AU - Christopoulos, Arthur

AU - Furness, Sebastian G.B.

AU - Miller, Laurence J.

AU - Reedtz-Runge, Steffen

AU - Langmead, Christopher J.

AU - Gloriam, David E.

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) (nos. 1126857, 1184726, 1160076, and 1150083). P.M.S. is a Senior Principal Research Fellow and D.W. a Senior Research Fellow of the NHMRC. R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO (18069571). D.E.G. was funded by the Lundbeck Foundation (R163-2013-16327) and A.J.K. from the Independent Research Fund Denmark (8021-00173B). This work was partially supported by the Monash University Ramaciotti Centre for cryoelectron microscopy and the Monash University MASSIVE high-performance computing facility. D.W. and P.M.S. conceived and formulated the research. X.Z. expressed and purified complexes; R.D. M.J.B. and H.V. performed sample vitrification and cryo-EM imaging; X.Z. M.J.B. and R.D. processed the EM data; X.Z. and M.J.B. generated atomic models; and X.Z. P.Z. T.T.T. S.Y.A. G.D.S. C.R.U. and T.E. generated DNA constructs and performed pharmacological assays. D.W. P.M.S. A.J.K. D.E.G. X.Z. and M.J.B. analyzed the receptor structures; D.W. X.Z. P.Z. C.R.U. and S.R.-R. analyzed pharmacological data. S.G.B.F. generated FLAG resin; P.Š. synthesized CHU-128. D.W. and P.M.S. supervised the project; A.G. and Y.-L.L. assisted complex biochemistry supervision; and P.Z. S.R.-R. and C.J.L. supervised pharmacological experiments. Project administration was provided by D.W. P.M.S. R.D. and S.R.-R. D.W. X.Z. M.J.B. A.J.K. R.D. and P.M.S. prepared figures and videos. D.W. P.M.S. X.Z. A.J.K. and D.E.G. wrote the manuscript draft. M.J.B. P.Z. T.T.T. S.Y.A. C.R.U. A.C. S.G.B.F. L.J.M. S.R.-R. C.J.L. and R.D. reviewed and edited the manuscript. D.W. P.M.S. R.D. and D.E.G. acquired the financial support for the project. C.R.U. T.E. and S.R.-R. are employees of Novo Nordisk. P.Š. is an employee of Apigenex. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) (nos. 1126857 , 1184726 , 1160076 , and 1150083 ). P.M.S. is a Senior Principal Research Fellow and D.W. a Senior Research Fellow of the NHMRC. R.D. was supported by Takeda Science Foundation 2019 Medical Research Grant and Japan Science and Technology Agency PRESTO ( 18069571 ). D.E.G. was funded by the Lundbeck Foundation ( R163-2013-16327 ) and A.J.K. from the Independent Research Fund Denmark ( 8021-00173B ). This work was partially supported by the Monash University Ramaciotti Centre for cryoelectron microscopy and the Monash University MASSIVE high-performance computing facility. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/11/5

Y1 - 2020/11/5

N2 - Zhang et al. show that the non-peptide GLP-1R agonist PF 06882961, but not CHU-128, was able to closely mimic the in vitro pharmacological fingerprint of GLP-1. These pharmacological activities could be rationalized from high-resolution structures that provide a novel template for the design of new agonists targeting the GLP-1R.

AB - Zhang et al. show that the non-peptide GLP-1R agonist PF 06882961, but not CHU-128, was able to closely mimic the in vitro pharmacological fingerprint of GLP-1. These pharmacological activities could be rationalized from high-resolution structures that provide a novel template for the design of new agonists targeting the GLP-1R.

KW - G-protein-coupled receptor

KW - GLP-1

KW - cryoelectron microscopy

KW - glucagon-like peptide-1 receptor

KW - non-peptide agonists

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AN - SCOPUS:85094955564

SN - 1097-2765

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SP - 485-500.e7

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Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists

Abstract

Keywords

ASJC Scopus subject areas

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