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

Department of Drug Design and Pharmacology

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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. / Zhang, Xin; Belousoff, Matthew J; Zhao, Peishen; Kooistra, Albert J; Truong, Tin T; Ang, Sheng Yu; Underwood, Christina Rye; Egebjerg, Thomas; Šenel, Petr; Stewart, Gregory D; Liang, Yi-Lynn; Glukhova, Alisa; Venugopal, Hari; Christopoulos, Arthur; Furness, Sebastian G B; Miller, Laurence J; Reedtz-Runge, Steffen; Langmead, Christopher J; Gloriam, David E; Danev, Radostin; Sexton, Patrick M; Wootten, Denise.

In: Molecular Cell, Vol. 80, No. 3, 2020, p. 485-500.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Zhang, X, Belousoff, MJ, Zhao, P, Kooistra, AJ, Truong, TT, Ang, SY, Underwood, CR, Egebjerg, T, Šenel, P, Stewart, GD, Liang, Y-L, 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. https://doi.org/10.1016/j.molcel.2020.09.020

APA

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. https://doi.org/10.1016/j.molcel.2020.09.020

Vancouver

Zhang X, Belousoff MJ, Zhao P, Kooistra AJ, Truong TT, Ang SY et al. Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. Molecular Cell. 2020;80(3):485-500. https://doi.org/10.1016/j.molcel.2020.09.020

Author

Zhang, Xin ; Belousoff, Matthew J ; Zhao, Peishen ; Kooistra, Albert J ; Truong, Tin T ; Ang, Sheng Yu ; Underwood, Christina Rye ; Egebjerg, Thomas ; Šenel, Petr ; Stewart, Gregory D ; Liang, Yi-Lynn ; Glukhova, Alisa ; Venugopal, Hari ; Christopoulos, Arthur ; Furness, Sebastian G B ; Miller, Laurence J ; Reedtz-Runge, Steffen ; Langmead, Christopher J ; Gloriam, David E ; Danev, Radostin ; Sexton, Patrick M ; Wootten, Denise. / Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists. In: Molecular Cell. 2020 ; Vol. 80, No. 3. pp. 485-500.

Bibtex

@article{d15f7c3233ae43b29d9db3809a50eb78,

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

abstract = "Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.",

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 Yi-Lynn Liang 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",

year = "2020",

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

language = "English",

volume = "80",

pages = "485--500",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "3",

}

RIS

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

PY - 2020

Y1 - 2020

N2 - Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

AB - Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

U2 - 10.1016/j.molcel.2020.09.020

DO - 10.1016/j.molcel.2020.09.020

M3 - Journal article

C2 - 33027691

VL - 80

SP - 485

EP - 500

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -

ID: 250599552