Insights into the Role of Asp792.50 in 尾2 Adrenergic Receptor Activation from Molecular Dynamics Simulations

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• 作者：Anirudh Ranganathan ; Ron O. Dror ; Jens Carlsson
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：November 25, 2014
• 年：2014
• 卷：53
• 期：46
• 页码：7283-7296
• 全文大小：498K
• ISSN：1520-4995

文摘

Achieving a molecular-level understanding of G-protein-coupled receptor (GPCR) activation has been a long-standing goal in biology and could be important for the development of novel drugs. Recent breakthroughs in structural biology have led to the determination of high-resolution crystal structures for the 尾₂ adrenergic receptor (尾₂AR) in inactive and active states, which provided an unprecedented opportunity to understand receptor signaling at the atomic level. We used molecular dynamics (MD) simulations to explore the potential roles of ionizable residues in 尾₂AR activation. One such residue is the strongly conserved Asp79^2.50, which is buried in a transmembrane cavity and becomes dehydrated upon 尾₂AR activation. MD free energy calculations based on 尾₂AR crystal structures suggested an increase in the population of the protonated state of Asp79^2.50 upon activation, which may contribute to the experimentally observed pH-dependent activation of this receptor. Analysis of MD simulations (in total >100 渭s) with two different protonation states further supported the conclusion that the protonated Asp79^2.50 shifts the conformation of the 尾₂AR toward more active-like states. On the basis of our calculations and analysis of other GPCR crystal structures, we suggest that the protonation state of Asp^2.50 may act as a functionally important microswitch in the activation of the 尾₂AR and other class A receptors.