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Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor
The human neuropeptide Y (NPY) Y(2) receptor (Y(2)R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y(2)R remains challenging with no success in clinical appli...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854658/ https://www.ncbi.nlm.nih.gov/pubmed/33531491 http://dx.doi.org/10.1038/s41467-021-21030-9 |
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author | Tang, Tingting Hartig, Christin Chen, Qiuru Zhao, Wenli Kaiser, Anette Zhang, Xuefeng Zhang, Hui Qu, Honge Yi, Cuiying Ma, Limin Han, Shuo Zhao, Qiang Beck-Sickinger, Annette G. Wu, Beili |
author_facet | Tang, Tingting Hartig, Christin Chen, Qiuru Zhao, Wenli Kaiser, Anette Zhang, Xuefeng Zhang, Hui Qu, Honge Yi, Cuiying Ma, Limin Han, Shuo Zhao, Qiang Beck-Sickinger, Annette G. Wu, Beili |
author_sort | Tang, Tingting |
collection | PubMed |
description | The human neuropeptide Y (NPY) Y(2) receptor (Y(2)R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y(2)R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y(2)R bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details of the ligand-binding mode of Y(2)R. Combined with mutagenesis studies, the Y(2)R structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound Y(1)R structures identified receptor-ligand interactions that play different roles in modulating receptor activation and mediating ligand selectivity. These findings deepen our understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors, and would enable structure-based drug design. |
format | Online Article Text |
id | pubmed-7854658 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78546582021-02-11 Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor Tang, Tingting Hartig, Christin Chen, Qiuru Zhao, Wenli Kaiser, Anette Zhang, Xuefeng Zhang, Hui Qu, Honge Yi, Cuiying Ma, Limin Han, Shuo Zhao, Qiang Beck-Sickinger, Annette G. Wu, Beili Nat Commun Article The human neuropeptide Y (NPY) Y(2) receptor (Y(2)R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y(2)R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y(2)R bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details of the ligand-binding mode of Y(2)R. Combined with mutagenesis studies, the Y(2)R structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound Y(1)R structures identified receptor-ligand interactions that play different roles in modulating receptor activation and mediating ligand selectivity. These findings deepen our understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors, and would enable structure-based drug design. Nature Publishing Group UK 2021-02-02 /pmc/articles/PMC7854658/ /pubmed/33531491 http://dx.doi.org/10.1038/s41467-021-21030-9 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Tang, Tingting Hartig, Christin Chen, Qiuru Zhao, Wenli Kaiser, Anette Zhang, Xuefeng Zhang, Hui Qu, Honge Yi, Cuiying Ma, Limin Han, Shuo Zhao, Qiang Beck-Sickinger, Annette G. Wu, Beili Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor |
title | Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor |
title_full | Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor |
title_fullStr | Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor |
title_full_unstemmed | Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor |
title_short | Structural basis for ligand recognition of the neuropeptide Y Y(2) receptor |
title_sort | structural basis for ligand recognition of the neuropeptide y y(2) receptor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854658/ https://www.ncbi.nlm.nih.gov/pubmed/33531491 http://dx.doi.org/10.1038/s41467-021-21030-9 |
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