Multi-state Model-Based Identification of Cryptic Allosteric Sites on Human Serotonin Transporter

变构调节 血清素转运体 鉴定(生物学) 5-羟色胺质膜转运蛋白 运输机 血清素 神经科学 计算生物学 生物 遗传学 基因 受体 生态学
作者
Gao Tu,Binbin Xu,Ding Luo,Jin Liu,Zerong Liu,Gang Chen,Weiwei Xue
出处
期刊:ACS Chemical Neuroscience [American Chemical Society]
卷期号:14 (9): 1686-1694 被引量:13
标识
DOI:10.1021/acschemneuro.3c00155
摘要

Serotonin transporter (SERT) plays a fundamental role in taking the synaptic cleft serotonin back to the presynaptic neuron. The discovery of allosteric SERT modulators represents the next-generation medication for psychiatric disorders such as depression. Here, based on the cryo-EM structures of ibogaine in complex with SERT in distinct conformations, the multiple functional structures of the transporter bound to serotonin, including outward-open (OOholo), outward-occluded (OCholo), and inward-open (IOholo and IOholo′), were carefully characterized by induced-fit docking Gaussian-accelerated molecular dynamics (IFD-GaMD) simulation and the free-energy landscape analysis. Further MM/GBSA binding free energy, per-residue contribution, and molecular interaction fingerprint calculations revealed the interaction variations of serotonin with SERT in functional structures, which confirmed the allostery of SERT during serotonin reuptake. Moreover, five unique cryptic allosteric sites, which are druggable and capable of targeting by small molecules, were identified on the characterized multistate structures. These results provide structural and energetic information for the molecular mechanism of serotonin reuptake and will provide opportunities for the development of novel therapeutics based on the identified new allosteric sites on SERT.
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