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Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR

Crystal and cryo-EM structures of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) bound with their peptide ligands have been obtained with full-length constructs, indicating that the extracellular domain (ECD) is indispensable for specific ligand binding. This article comp...

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Autores principales: Wang, Huixia, Hu, Wanhui, Xu, Tiandan, Yuan, Ya, Liu, Dongsheng, Wüthrich, Kurt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10276138/
https://www.ncbi.nlm.nih.gov/pubmed/37332600
http://dx.doi.org/10.1016/j.isci.2023.106918
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author Wang, Huixia
Hu, Wanhui
Xu, Tiandan
Yuan, Ya
Liu, Dongsheng
Wüthrich, Kurt
author_facet Wang, Huixia
Hu, Wanhui
Xu, Tiandan
Yuan, Ya
Liu, Dongsheng
Wüthrich, Kurt
author_sort Wang, Huixia
collection PubMed
description Crystal and cryo-EM structures of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) bound with their peptide ligands have been obtained with full-length constructs, indicating that the extracellular domain (ECD) is indispensable for specific ligand binding. This article complements these data with studies of ligand recognition of the two receptors in solution. Paramagnetic NMR relaxation enhancement measurements using dual labeling with fluorine-19 probes on the receptor and nitroxide spin labels on the peptide ligands provided new insights. The glucagon-like peptide-1 (GLP-1) was found to interact with GLP-1R by selective binding to the extracellular surface. The ligand selectivity toward the extracellular surface of the receptor was preserved in the transmembrane domain (TMD) devoid of the ECD. The dual labeling approach further provided evidence of cross-reactivity of GLP-1R and GCGR with glucagon and GLP-1, respectively, which is of interest in the context of medical treatments using combinations of the two polypeptides.
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spelling pubmed-102761382023-06-18 Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR Wang, Huixia Hu, Wanhui Xu, Tiandan Yuan, Ya Liu, Dongsheng Wüthrich, Kurt iScience Article Crystal and cryo-EM structures of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) bound with their peptide ligands have been obtained with full-length constructs, indicating that the extracellular domain (ECD) is indispensable for specific ligand binding. This article complements these data with studies of ligand recognition of the two receptors in solution. Paramagnetic NMR relaxation enhancement measurements using dual labeling with fluorine-19 probes on the receptor and nitroxide spin labels on the peptide ligands provided new insights. The glucagon-like peptide-1 (GLP-1) was found to interact with GLP-1R by selective binding to the extracellular surface. The ligand selectivity toward the extracellular surface of the receptor was preserved in the transmembrane domain (TMD) devoid of the ECD. The dual labeling approach further provided evidence of cross-reactivity of GLP-1R and GCGR with glucagon and GLP-1, respectively, which is of interest in the context of medical treatments using combinations of the two polypeptides. Elsevier 2023-05-19 /pmc/articles/PMC10276138/ /pubmed/37332600 http://dx.doi.org/10.1016/j.isci.2023.106918 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Wang, Huixia
Hu, Wanhui
Xu, Tiandan
Yuan, Ya
Liu, Dongsheng
Wüthrich, Kurt
Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR
title Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR
title_full Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR
title_fullStr Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR
title_full_unstemmed Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR
title_short Selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class B GPCRs GLP-1R and GCGR
title_sort selective polypeptide ligand binding to the extracellular surface of the transmembrane domains of the class b gpcrs glp-1r and gcgr
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10276138/
https://www.ncbi.nlm.nih.gov/pubmed/37332600
http://dx.doi.org/10.1016/j.isci.2023.106918
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