title: A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2.
abstract: 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(2A)R) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT(2A)R 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(2A)R agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT(2A)R 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(2A)R activation.
authors.affiliation: Department of Physiology and Biophysics and §The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Perez-Aguilar
authors.forename: Jufang
authors.initials: J
authors.lastname: Shan
authors.forename: Michael V
authors.initials: MV
authors.lastname: LeVine
authors.forename: George
authors.initials: G
authors.lastname: Khelashvili
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D001665:Binding Sites; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists