{"title":"B 型内皮素受体与 Gs、Gi 和 Gq 相互作用的分子机制","authors":"","doi":"10.1016/j.str.2024.06.020","DOIUrl":null,"url":null,"abstract":"<p>The endothelin receptor type B (ET<sub>B</sub>) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ET<sub>B</sub> activation. ET<sub>B</sub> coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ET<sub>B</sub> in ET<sub>B</sub>-Gi1 or ET<sub>B</sub>-Gq coupling. Although The C terminus of Gα is essential for ET<sub>B</sub>-Gi1 and ET<sub>B</sub>-Gq coupling, ET<sub>B</sub> ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ET<sub>B</sub> with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ET<sub>B</sub>-induced activation.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq\",\"authors\":\"\",\"doi\":\"10.1016/j.str.2024.06.020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>The endothelin receptor type B (ET<sub>B</sub>) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ET<sub>B</sub> activation. ET<sub>B</sub> coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ET<sub>B</sub> in ET<sub>B</sub>-Gi1 or ET<sub>B</sub>-Gq coupling. Although The C terminus of Gα is essential for ET<sub>B</sub>-Gi1 and ET<sub>B</sub>-Gq coupling, ET<sub>B</sub> ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ET<sub>B</sub> with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ET<sub>B</sub>-induced activation.</p>\",\"PeriodicalId\":22168,\"journal\":{\"name\":\"Structure\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-07-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Structure\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.str.2024.06.020\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Structure","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.str.2024.06.020","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
B 型内皮素受体（ETB）表现出与各种异三聚体 G 蛋白亚型（包括 Gs、Gi/o、Gq/11 和 G12/13）的杂乱耦合。最近的荧光和结构研究提出了有关这些 G 蛋白亚型的耦合效率和决定因素的问题。在此，我们利用一种综合方法，结合氢/氘交换质谱法和基于 NanoLuc 二进制技术的细胞系统，研究了 ETB 激活引发的 Gs、Gi 和 Gq 的构象变化。ETB 与 Gi 和 Gq 相耦合，但不与 Gs 相耦合。我们强调了特定区域在 ETB-Gi1 或 ETB-Gq 偶联中的关键作用，包括 Gα 的 C 末端和 ETB 的胞内环 2（ICL2）。虽然 Gα 的 C 末端对 ETB-Gi1 和 ETB-Gq 耦合至关重要，但 ETB ICL2 会影响 Gq 耦合，而不会影响 Gi1 耦合。我们的研究结果表明，ETB 与 Gs、Gi1 和 Gq 的耦合效率不同，在 ETB 诱导的激活过程中 G 蛋白的构象也会发生不同的变化。
Molecular mechanism of the endothelin receptor type B interactions with Gs, Gi, and Gq
The endothelin receptor type B (ETB) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ETB activation. ETB coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ETB in ETB-Gi1 or ETB-Gq coupling. Although The C terminus of Gα is essential for ETB-Gi1 and ETB-Gq coupling, ETB ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ETB with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ETB-induced activation.
期刊介绍：
Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome.
In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.
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