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

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• 作者：Jose Manuel Perez-Aguilar ; Jufang Shan ; Michael V. LeVine ; George Khelashvili ; Harel Weinstein
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：November 12, 2014
• 年：2014
• 卷：136
• 期：45
• 页码：16044-16054
• 全文大小：629K
• ISSN：1520-5126

文摘

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-HT_2AR) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT_2AR 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-HT_2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT_2AR 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-HT_2AR activation.