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Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24
Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orth...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171782/ https://www.ncbi.nlm.nih.gov/pubmed/35561211 http://dx.doi.org/10.1073/pnas.2200155119 |
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author | Cong, Zhaotong Zhou, Qingtong Li, Yang Chen, Li-Nan Zhang, Zi-Chen Liang, Anyi Liu, Qing Wu, Xiaoyan Dai, Antao Xia, Tian Wu, Wei Zhang, Yan Yang, Dehua Wang, Ming-Wei |
author_facet | Cong, Zhaotong Zhou, Qingtong Li, Yang Chen, Li-Nan Zhang, Zi-Chen Liang, Anyi Liu, Qing Wu, Xiaoyan Dai, Antao Xia, Tian Wu, Wei Zhang, Yan Yang, Dehua Wang, Ming-Wei |
author_sort | Cong, Zhaotong |
collection | PubMed |
description | Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and G(s) protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R. |
format | Online Article Text |
id | pubmed-9171782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-91717822022-06-08 Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 Cong, Zhaotong Zhou, Qingtong Li, Yang Chen, Li-Nan Zhang, Zi-Chen Liang, Anyi Liu, Qing Wu, Xiaoyan Dai, Antao Xia, Tian Wu, Wei Zhang, Yan Yang, Dehua Wang, Ming-Wei Proc Natl Acad Sci U S A Biological Sciences Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and G(s) protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R. National Academy of Sciences 2022-05-13 2022-05-17 /pmc/articles/PMC9171782/ /pubmed/35561211 http://dx.doi.org/10.1073/pnas.2200155119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Cong, Zhaotong Zhou, Qingtong Li, Yang Chen, Li-Nan Zhang, Zi-Chen Liang, Anyi Liu, Qing Wu, Xiaoyan Dai, Antao Xia, Tian Wu, Wei Zhang, Yan Yang, Dehua Wang, Ming-Wei Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 |
title | Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 |
title_full | Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 |
title_fullStr | Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 |
title_full_unstemmed | Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 |
title_short | Structural basis of peptidomimetic agonism revealed by small-molecule GLP-1R agonists Boc5 and WB4-24 |
title_sort | structural basis of peptidomimetic agonism revealed by small-molecule glp-1r agonists boc5 and wb4-24 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171782/ https://www.ncbi.nlm.nih.gov/pubmed/35561211 http://dx.doi.org/10.1073/pnas.2200155119 |
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