Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction.
Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction.
复制标题
GPCR 的激素肽激活机制：范德华吸引力引发 AT1R 的血管紧张素 II 激活状态。
DOI：
10.1021/acs.jcim.8b00583
复制
发表时间：
2019
影响因子：
5.6
通讯作者：
Karnik,SadashivaS
中科院分区：
文献类型：
--
作者：
Singh,KhuraijamDhanachandra;Unal,Hamiyet;Desnoyer,Russell;Karnik,SadashivaS
我们提出了一系列的结构变化参与激素肽激活的原型GPCR。微秒分子动力学模拟生成的构象集合揭示了通过与天然激素结合的人AT1R内的关键"微动开关"的结构变化的传播。内分泌八肽血管紧张素II（AngII）激活我们体内的AT1R信号，维持生理血压，电解质平衡和心血管稳态。过度的AT1R激活与高血压和心血管疾病的发病机制有关，这些疾病通过沙坦类药物治疗。沙坦类药物抑制AT1R的机制已通过2.8 μ m X射线结构、诱变和计算分析阐明。然而，血管紧张素Ⅱ激活AT1R的机制尚不清楚。目前的研究描绘了一个激活计划发起的AngII结合。AT1R中Phe 8 AngII与Ile 2887.39之间的货车范德华"抓握"相互作用诱导了机械应变拉伸Tyr 2927.43和关键螺旋间氢键的断裂，首先是Tyr 2927.43和Val 1083.32之间，其次是Asn 1113.35和Asn 2957.46之间。随后在AT1R中的保守微型开关DRYTM 3、Yx7K（R）TM 5、CWxPTM 6和NPxxYTM 7中观察到变化。激活AT1R细胞内区域的微开关可以触发G蛋白结合口袋的形成以及螺旋-8暴露于细胞质。因此，AT1 R的活性样构象是由Phe 8 AngII与Ile 2887.39的货车范德华相互作用引发的，随后是关键螺旋间氢键的系统重组和微动开关的激活。
We present a succession of structural changes involved in hormone peptide activation of a prototypical GPCR. Microsecond molecular dynamics simulation generated conformational ensembles reveal propagation of structural changes through key “microswitches” within human AT1R bound to native hormone. The endocrine octa-peptide angiotensin II (AngII) activates AT1R signaling in our bodies which maintains physiological blood pressure, electrolyte balance, and cardiovascular homeostasis. Excessive AT1R activation is associated with pathogenesis of hypertension and cardiovascular diseases which are treated by sartan drugs. The mechanism of AT1R inhibition by sartans has been elucidated by 2.8 Å X-ray structures, mutagenesis, and computational analyses. Yet, the mechanism of AT1R activation by AngII is unclear. The current study delineates an activation scheme initiated by AngII binding. A van der Waals “grasp” interaction between Phe8AngIIwith Ile2887.39in AT1R induced mechanical strain pulling Tyr2927.43and breakage of critical interhelical H-bonds, first between Tyr2927.43and Val1083.32and second between Asn1113.35and Asn2957.46. Subsequently changes are observed in conserved microswitches DRYTM3, Yx7K(R)TM5, CWxPTM6, and NPxxYTM7in AT1R. Activating the microswitches in the intracellular region of AT1R may trigger formation of the G-protein binding pocket as well as exposure of helix-8 to cytoplasm. Thus, the active-like conformation of AT1R is initiated by the van der Waals interaction of Phe8AngIIwith Ile2887.39, followed by systematic reorganization of critical interhelical H-bonds and activation of microswitches.