Structure and dynamics of the active Gs-coupled human secretin receptor
Structure and dynamics of the active Gs-coupled human secretin receptor
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DOI：
10.1038/s41467-020-17791-4
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发表时间：
2020-08-18
影响因子：
16.6
通讯作者：
Miller, Laurence J.
中科院分区：
文献类型：
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作者：
Dong, Maoqing;Deganutti, Giuseppe;Miller, Laurence J.
B类促胰液素GPCR(Secr)具有广泛的生理作用，具有治疗代谢和心血管疾病的靶向潜力。了解SECR结合和激活的分子机制对其治疗开发具有重要意义。我们结合冷冻电子显微镜、分子动力学和生物化学交联法来确定与secr：GS复合体结合的促胰液素的2.3埃结构和询问动力学。相对于其7-跨膜(TM)核心，SECR显示了其胞外区(ECD)的独特组织结构，形成了比其他家族成员更广泛的相互作用。促胰液素与受体细胞外环(ECL)和TM螺旋之间形成了大量的极性相互作用。半胱氨酸交联、冷冻电子显微镜多变量分析和分子动力学模拟表明，多肽与受体之间的相互作用是动态的，并提出了一个多肽的初始结合模型，其中多肽的远N端与SecR ECL2的早期相互作用可能发生在多肽C端与ECD的初始结合之后。
The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 angstrom structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD.