Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois, United States of America.
Zoetis Inc, Kalamazoo, Michigan, United States of America.
PLoS One. 2020 Dec 9;15(12):e0243313. doi: 10.1371/journal.pone.0243313. eCollection 2020.
G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a ∼110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only ∼24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.
G 蛋白偶联受体（GPCRs）介导细胞内信号转导，以响应细胞外配体结合，并且是三分之一已批准药物的靶标。配体结合通过优先稳定活性或非活性构象来调节 GPCR 分子的自由能景观，从而决定细胞内蛋白募集和下游信号转导。我们进行增强采样分子动力学模拟，以恢复在非配体形式以及与致幻剂麦角酸二乙酰胺（LSD）激动剂和利舒必利拮抗剂结合的热稳定突变体 5-羟色胺受体 5-HT2B 的自由能表面。LSD 结合赋予约 110 kJ/mol 的驱动力，使构象重排进入活性状态。利舒必利结合形式在结构上与无配体形式相似，仅稳定约 24 kJ/mol。这项工作量化了 5-HT2B 配体诱导的构象特异性和功能选择性，并为配体的高通量虚拟筛选和配体结合分子自由能景观的合理工程提供了平台。
