Department of Pharmacological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
Center for Molecular Biophysics, Biosciences Division , Oak Ridge National Laboratory , Oak Ridge , Tennessee 37830 , United States.
J Phys Chem B. 2019 Sep 26;123(38):7947-7954. doi: 10.1021/acs.jpcb.9b04474. Epub 2019 Sep 12.
Sodium ions have long been known to reduce the binding of agonists in many class-A GPCRs while having little effect on antagonist binding. Here, using long-time scale classical all-atom molecular dynamics simulations, we explore, in atomic detail, the motion of sodium ions within the ligand-binding pocket of the A adenosine receptor (A2A-AR) both in the presence and absence of ligands and in the active and inactive state. We identify novel secondary ion binding sites within the pocket and find that the types of ion motions within the pocket are highly dependent on the presence and type of ligand within the pocket. Our results provide a first step toward developing a molecular understanding of the impact of sodium ions on class-A GPCRs.
钠离子长期以来被认为可以降低许多 A 类 GPCR 中激动剂的结合，而对拮抗剂的结合影响很小。在这里，我们使用长时间尺度的经典全原子分子动力学模拟，以原子细节的方式探索了钠离子在 A 腺苷受体（A2A-AR）配体结合口袋内的运动，包括有配体和无配体、激活态和失活态的情况。我们在口袋内识别出了新的次级离子结合位点，并发现口袋内离子的运动类型高度依赖于口袋内配体的存在和类型。我们的结果为发展对 A 类 GPCR 中钠离子影响的分子理解迈出了第一步。
