A Functional Selectivity Mechanism at the Serotonin-2A GPCR Involves Ligand-Dependent Conformations of Intracellular Loop 2

被引:59
作者
Perez-Aguilar, Jose Manuel [1 ]
Shan, Jufang [1 ]
LeVine, Michael V. [1 ]
Khelashvili, George [1 ]
Weinstein, Harel [1 ,2 ]
机构
[1] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
[2] Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
PROTEIN-COUPLED RECEPTORS; MOLECULAR-DYNAMICS; BETA(2)-ADRENERGIC RECEPTOR; CRYSTAL-STRUCTURE; SIGNALING PATHWAYS; 5-HYDROXYTRYPTAMINE(2A) RECEPTOR; STRUCTURAL INSIGHTS; OPIOID RECEPTOR; IN-VIVO; ACTIVATION;
D O I
10.1021/ja508394x
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT2AR) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. The findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT2AR activation.
引用
收藏
页码:16044 / 16054
页数:11
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