Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor

被引:2
|
作者
Peters, Brandon L. [1 ]
Deng, Jinxia [2 ]
Ferguson, Andrew L. [1 ]
机构
[1] Univ Chicago, Pritzker Sch Mol Engn, Chicago, IL 60637 USA
[2] Zoetis Inc, Kalamazoo, MI USA
来源
PLOS ONE | 2020年 / 15卷 / 12期
基金
美国国家科学基金会;
关键词
MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; BINDING; ACTIVATION; AGONIST; GPCRS; STATE;
D O I
10.1371/journal.pone.0243313
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 similar to 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 similar to 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.
引用
收藏
页数:21
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