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PMID: 22532793 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Ligand-dependent conformations and dynamics of the serotonin 5-HT(2A) receptor determine its activation and membrane-driven oligomerization properties.

PLoS computational biology ·Vol. 8 ·No. 4 ·2012-00-00 ·Pages e1002473

Shan J, Khelashvili G, Mondal S, Mehler EL, Weinstein H

Abstract

From computational simulations of a serotonin 2A receptor (5-HT(2A)R) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT(2A)R, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization.

MeSH Terms
Binding Sites Cell Membrane/chemistry Computer Simulation Ketanserin/chemistry Ligands Lysergic Acid Diethylamide/chemistry Models, Chemical Models, Molecular Protein Binding Protein Conformation Receptor, Serotonin, 5-HT2A/chemistry,ultrastructure Serotonin/chemistry Structure-Activity Relationship
Chemicals
Ligands Receptor, Serotonin, 5-HT2A Serotonin Lysergic Acid Diethylamide Ketanserin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Shan Jufang
Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, United States of America.
Khelashvili George
Mondal Sayan
Mehler Ernest L
Weinstein Harel
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Article Info
Journal
PLoS computational biology
Abbr.
PLoS Comput Biol
ISSN
1553-7358
DOI
10.1371/journal.pcbi.1002473
Published
2012-00-00
Epub
2012-00-19
Pages
e1002473
Language
English
Region
United States
NLM ID
101238922
PMCID
PMC3330085
Subset
IM
Grants
NIDA NIH HHS · P01 DA012923 · United States
NIDA NIH HHS · R01 DA015170 · United States
NIDA NIH HHS · P01 DA-012923 · United States
External Links
PubMed source DOI: 10.1371/journal.pcbi.1002473 PMC Full Text View journal details
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