Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

Jiang Wang; Dehua Yang; Xi Cheng; Linlin Yang; Zhaohui Wang; Antao Dai; Xiaoqing Cai; Chao Zhang; Elita Yuliantie; Qiaofeng Liu; Hualiang Jiang; Hong Liu; Ming Wei Wang; Huaiyu Yang

doi:10.1021/acschembio.1c00552

Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

Jiang Wang
, Dehua Yang
, Xi Cheng
, Linlin Yang
, Zhaohui Wang
, Antao Dai
, Xiaoqing Cai
, Chao Zhang
, Elita Yuliantie
, Qiaofeng Liu
, Hualiang Jiang
, Hong Liu^*
, Ming Wei Wang^*
, Huaiyu Yang^*

^*Corresponding author for this work

School of Life Sciences

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

15 Scopus citations

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.

Original language	English
Pages (from-to)	2444-2452
Number of pages	9
Journal	ACS Chemical Biology
Volume	16
Issue number	11
DOIs	https://doi.org/10.1021/acschembio.1c00552
State	Published - 19 Nov 2021

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10.1021/acschembio.1c00552

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title = "Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site",

abstract = "The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.",

author = "Jiang Wang and Dehua Yang and Xi Cheng and Linlin Yang and Zhaohui Wang and Antao Dai and Xiaoqing Cai and Chao Zhang and Elita Yuliantie and Qiaofeng Liu and Hualiang Jiang and Hong Liu and Wang, \{Ming Wei\} and Huaiyu Yang",

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month = nov,

day = "19",

doi = "10.1021/acschembio.1c00552",

language = "英语",

volume = "16",

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T1 - Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

AU - Wang, Jiang

AU - Yang, Dehua

AU - Cheng, Xi

AU - Yang, Linlin

AU - Wang, Zhaohui

AU - Dai, Antao

AU - Cai, Xiaoqing

AU - Zhang, Chao

AU - Yuliantie, Elita

AU - Liu, Qiaofeng

AU - Jiang, Hualiang

AU - Liu, Hong

AU - Wang, Ming Wei

AU - Yang, Huaiyu

PY - 2021/11/19

Y1 - 2021/11/19

N2 - The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.

AB - The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.

UR - https://www.scopus.com/pages/publications/85117244756

U2 - 10.1021/acschembio.1c00552

DO - 10.1021/acschembio.1c00552

M3 - 文章

C2 - 34570476

AN - SCOPUS:85117244756

SN - 1554-8929

VL - 16

SP - 2444

EP - 2452

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 11

ER -

Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site

Abstract

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