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Structural insights into ligand recognition and selectivity of somatostatin receptors
Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse re...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Nature Singapore
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343605/ https://www.ncbi.nlm.nih.gov/pubmed/35739238 http://dx.doi.org/10.1038/s41422-022-00679-x |
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author | Zhao, Wenli Han, Shuo Qiu, Na Feng, Wenbo Lu, Mengjie Zhang, Wenru Wang, Mu Zhou, Qingtong Chen, Shutian Xu, Wei Du, Juan Chu, Xiaojing Yi, Cuiying Dai, Antao Hu, Liaoyuan Shen, Michelle Y. Sun, Yaping Zhang, Qing Ma, Yingli Zhong, Wenge Yang, Dehua Wang, Ming-Wei Wu, Beili Zhao, Qiang |
author_facet | Zhao, Wenli Han, Shuo Qiu, Na Feng, Wenbo Lu, Mengjie Zhang, Wenru Wang, Mu Zhou, Qingtong Chen, Shutian Xu, Wei Du, Juan Chu, Xiaojing Yi, Cuiying Dai, Antao Hu, Liaoyuan Shen, Michelle Y. Sun, Yaping Zhang, Qing Ma, Yingli Zhong, Wenge Yang, Dehua Wang, Ming-Wei Wu, Beili Zhao, Qiang |
author_sort | Zhao, Wenli |
collection | PubMed |
description | Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G(i1)-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G(i1)-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs. |
format | Online Article Text |
id | pubmed-9343605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer Nature Singapore |
record_format | MEDLINE/PubMed |
spelling | pubmed-93436052022-08-03 Structural insights into ligand recognition and selectivity of somatostatin receptors Zhao, Wenli Han, Shuo Qiu, Na Feng, Wenbo Lu, Mengjie Zhang, Wenru Wang, Mu Zhou, Qingtong Chen, Shutian Xu, Wei Du, Juan Chu, Xiaojing Yi, Cuiying Dai, Antao Hu, Liaoyuan Shen, Michelle Y. Sun, Yaping Zhang, Qing Ma, Yingli Zhong, Wenge Yang, Dehua Wang, Ming-Wei Wu, Beili Zhao, Qiang Cell Res Article Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G(i1)-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G(i1)-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs. Springer Nature Singapore 2022-06-23 2022-08 /pmc/articles/PMC9343605/ /pubmed/35739238 http://dx.doi.org/10.1038/s41422-022-00679-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhao, Wenli Han, Shuo Qiu, Na Feng, Wenbo Lu, Mengjie Zhang, Wenru Wang, Mu Zhou, Qingtong Chen, Shutian Xu, Wei Du, Juan Chu, Xiaojing Yi, Cuiying Dai, Antao Hu, Liaoyuan Shen, Michelle Y. Sun, Yaping Zhang, Qing Ma, Yingli Zhong, Wenge Yang, Dehua Wang, Ming-Wei Wu, Beili Zhao, Qiang Structural insights into ligand recognition and selectivity of somatostatin receptors |
title | Structural insights into ligand recognition and selectivity of somatostatin receptors |
title_full | Structural insights into ligand recognition and selectivity of somatostatin receptors |
title_fullStr | Structural insights into ligand recognition and selectivity of somatostatin receptors |
title_full_unstemmed | Structural insights into ligand recognition and selectivity of somatostatin receptors |
title_short | Structural insights into ligand recognition and selectivity of somatostatin receptors |
title_sort | structural insights into ligand recognition and selectivity of somatostatin receptors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343605/ https://www.ncbi.nlm.nih.gov/pubmed/35739238 http://dx.doi.org/10.1038/s41422-022-00679-x |
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