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-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 selectivemore »
- Authors:
-
- Weill Medical College of Cornell Univ., New York, NY (United States)
- Publication Date:
- Research Org.:
- Cornell Univ., Ithaca, NY (United States). Weill Medical College
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1345813
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of the American Chemical Society
- Additional Journal Information:
- Journal Volume: 136; Journal Issue: 45; Journal ID: ISSN 0002-7863
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
Citation Formats
Perez-Aguilar, Jose Manuel, Shan, Jufang, LeVine, Michael V., Khelashvili, George, and Weinstein, Harel. A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2. United States: N. p., 2014.
Web. doi:10.1021/ja508394x.
Perez-Aguilar, Jose Manuel, Shan, Jufang, LeVine, Michael V., Khelashvili, George, & Weinstein, Harel. A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2. United States. https://doi.org/10.1021/ja508394x
Perez-Aguilar, Jose Manuel, Shan, Jufang, LeVine, Michael V., Khelashvili, George, and Weinstein, Harel. Tue .
"A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2". United States. https://doi.org/10.1021/ja508394x. https://www.osti.gov/servlets/purl/1345813.
@article{osti_1345813,
title = {A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2},
author = {Perez-Aguilar, Jose Manuel and Shan, Jufang and LeVine, Michael V. and Khelashvili, George and Weinstein, Harel},
abstractNote = {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. Lastly, 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.},
doi = {10.1021/ja508394x},
journal = {Journal of the American Chemical Society},
number = 45,
volume = 136,
place = {United States},
year = {Tue Oct 14 00:00:00 EDT 2014},
month = {Tue Oct 14 00:00:00 EDT 2014}
}
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Energy Landscapes as a Tool to Integrate GPCR Structure, Dynamics, and Function
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Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties
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The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems
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Analysis of positive and negative allosteric modulation in metabotropic glutamate receptors 4 and 5 with a dual ligand
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Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics
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Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors
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