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对生长激素释放激素受体（GHSR）及其配体界面的微观观察。

An atomic look at the interface of GHSR and its partners.

作者信息

Barreto Carlos A V, Moreira Irina S

机构信息

PhD Programme in Experimental Biology and Biomedicine, Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, Coimbra 3030-789 , Portugal.

CNC - Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra 3004-504, Portugal.

出版信息

Comput Struct Biotechnol J. 2024 Nov 22;23:4242-4251. doi: 10.1016/j.csbj.2024.11.035. eCollection 2024 Dec.

DOI:10.1016/j.csbj.2024.11.035
PMID:39660221
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11629268/
Abstract

G protein-coupled receptors (GPCRs) regulate cellular activity by transducing external signals and selectively coupling them to intracellular partners. Ghrelin receptor (GHSR) has garnered significant interest over the past decade owing to its diverse functional roles. In this study, we simulated five distinct GHSR-partner complexes, including G, G, and arrestin in two conformational states, to investigate the structural determinants of partner coupling. Interface and contact analyses revealed conserved interaction sites and novel interactions that were specific to each partner family. Molecular dynamics simulations provided insights into GHSR conformational dynamics, highlighting notable differences in key structural regions across complexes, such as the TM5 bulge. Our findings underscore the structural diversity of GHSR coupling mechanisms and contribute to a deeper understanding of their functional versatility.

摘要

G蛋白偶联受体（GPCRs）通过转导外部信号并将其选择性地与细胞内伴侣偶联来调节细胞活性。过去十年间，胃饥饿素受体（GHSR）因其多样的功能作用而备受关注。在本研究中，我们模拟了五种不同的GHSR-伴侣复合物，包括处于两种构象状态的G、G和抑制蛋白，以研究伴侣偶联的结构决定因素。界面和接触分析揭示了保守的相互作用位点以及每个伴侣家族特有的新型相互作用。分子动力学模拟为GHSR的构象动力学提供了见解，突出了不同复合物关键结构区域（如TM5凸起）的显著差异。我们的研究结果强调了GHSR偶联机制的结构多样性，并有助于更深入地理解其功能多样性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/c577b4b55f4f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/1332dc663d47/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/f037d256d8e1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/26e111ac45b3/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/55fb8ddf29e5/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/51ded1a6b07e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/c577b4b55f4f/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/1332dc663d47/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/f037d256d8e1/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/26e111ac45b3/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/55fb8ddf29e5/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/51ded1a6b07e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/994e/11629268/c577b4b55f4f/gr5.jpg

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本文引用的文献

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GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach.基于计算生物学方法的 G 蛋白偶联受体全基因组分析研究 G 蛋白偶联多样性。
Nat Commun. 2023 Jul 19;14(1):4361. doi: 10.1038/s41467-023-40045-y.
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Dynamic spatiotemporal determinants modulate GPCR:G protein coupling selectivity and promiscuity.
动态时空决定因素调节 GPCR：G 蛋白偶联的选择性和混杂性。
Nat Commun. 2022 Dec 2;13(1):7428. doi: 10.1038/s41467-022-34055-5.
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GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources.2023 年的 GPCRdb：使用 AlphaFold2 和新配体资源的特定状态结构模型。
Nucleic Acids Res. 2023 Jan 6;51(D1):D395-D402. doi: 10.1093/nar/gkac1013.
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Molecular mechanism of agonism and inverse agonism in ghrelin receptor.胃饥饿素受体激动和反向激动的分子机制。
Nat Commun. 2022 Jan 13;13(1):300. doi: 10.1038/s41467-022-27975-9.
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Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren.人源 ghrelin 受体受 ghrelin 和合成激动剂 ibutamoren 激活的结构基础。
Nat Commun. 2021 Nov 4;12(1):6410. doi: 10.1038/s41467-021-26735-5.
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