生物
细胞外
结合位点
元动力学
生物化学
生物物理学
分子动力学
化学
计算化学
作者
Aslihan Shenol,Michael Lückmann,Mette Trauelsen,Matteo Lambrughi,Matteo Tiberti,Elena Papaleo,Thomas M. Frimurer,Thue W. Schwartz
标识
DOI:10.1016/j.molcel.2024.01.011
摘要
SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) and mutagenesis across human, mouse, and rat SUCNR1, we characterize how a five-arginine motif around the extracellular pole of TM-VI determines the initial capture of succinate in the extracellular vestibule (ECV) to either stay or move down to the orthosteric site. Metadynamics demonstrate low-energy succinate binding in both sites, with an energy barrier corresponding to an intermediate stage during which succinate, with an associated water cluster, unlocks the hydrogen-bond-stabilized conformationally constrained extracellular loop (ECL)-2b. Importantly, simultaneous binding of two succinate molecules through either a “sequential” or “bypassing” mode is a frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters SUCNR1 between TM-I and -II and does not unlock ECL-2b. It is proposed that occupancy of both high-affinity sites is required for selective activation of SUCNR1 by high local succinate concentrations.
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