Activation Mechanism of Corticotrophin Releasing Factor Receptor Type 1 Elucidated Using Molecular Dynamics Simulations
Activation Mechanism of Corticotrophin Releasing Factor Receptor Type 1 Elucidated Using Molecular Dynamics Simulations
复制标题
利用分子动力学模拟阐明促肾上腺皮质激素释放因子受体 1 型的激活机制
DOI：
10.1021/acschemneuro.1c00126
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发表时间：
2021
影响因子：
5
通讯作者：
Wu, Chun
中科院分区：
文献类型：
--
作者：
Uba, Abdullahi Ibrahim;Scorese, Nicolas;Dean, Emily;Liu, Haiguang;Wu, Chun
促肾上腺皮质激素释放因子受体1型（CRF1R）是B类g蛋白偶联受体（gpcr）的一员，是治疗抑郁、焦虑和其他应激相关神经疾病的良好药物靶点。然而，迄今为止还没有批准的靶向CRF1R的药物，部分原因是结构信息不足以及其难以捉摸的激活机制。本文以CRF1R的跨膜结构域（TMD）和n端胞外结构域（ECD）的晶体结构为模板，建立了CRF1R的全长同源性模型，并对其与肽激动剂尿皮质素1或小分子拮抗剂CP-376395的配合物进行了全原子分子动力学模拟。我们通过模拟观察到TMD中保存完好的螺旋内容物，而跨膜（TM）螺旋显示出明显的重排。在激动剂结合的CRF1R系统中，TM6的TM重排尤为明显。观察到的构象变化可能是由于TMD中螺旋间/区域间氢键的断裂。动态网络分析确定了与TM6有高连接的社区。模拟结果显示，Y3566.53、Q3847.49和L3957.60三个关键残基与实验诱变数据一致，提示在受体激活中发挥重要作用。观察到的大规模构象变化与受体激动剂结合激活CRF1R有关，为配体设计提供指导。
The corticotropin-releasing factor receptor type 1 (CRF1R), a member of class B G-protein-coupled receptors (GPCRs), is a good drug target for treating depression, anxiety, and other stress-related neurodisorders. However, there is no approved drug targeting the CRF1R to date, partly due to inadequate structural information and its elusive activation mechanism. Here, by use of the crystal structures of its transmembrane domain (TMD) and the N-terminal extracellular domain (ECD) as a template, a full-length homology model of CRF1R was built and its complexes with peptide agonist urocortin 1 or small molecule antagonist CP-376395 were subjected to all-atom molecular dynamics simulations. We observed well preserved helical contents in the TMD through simulations, while the transmembrane (TM) helices showed clear rearrangements. The TM rearrangement is especially pronounced for the TM6 in the agonist-bound CRF1R system. The observed conformational changes are likely due to breakage of interhelical/inter-regional hydrogen bonds in the TMD. Dynamical network analysis identifies communities with high connections to TM6. Simulations reveal three key residues, Y3566.53, Q3847.49, and L3957.60, which corroborate experimental mutagenesis data, implying the important roles in the receptor activation. The observed large-scale conformational changes are related to CRF1R activation by agonist binding, providing guidance for ligand design.