Document Detail


Asymmetric ligand binding facilitates conformational transitions in pentameric ligand-gated ion channels.
MedLine Citation:
PMID:  23339564     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The anesthetic propofol inhibits the currents of the homopentameric ligand-gated ion channel GLIC, yet the crystal structure of GLIC with five propofol molecules bound symmetrically shows an open-channel conformation. To address this dilemma and determine if the symmetry of propofol binding sites affects the channel conformational transition, we performed a total of 1.5 μs of molecular dynamics simulations for different GLIC systems with propofol occupancies of 0, 1, 2, 3, and 5. GLIC without propofol binding or with five propofol molecules bound symmetrically, showed similar channel conformation and hydration status over multiple replicates of 100-ns simulations. In contrast, asymmetric binding to one, two or three equivalent sites in different subunits accelerated the channel dehydration, increased the conformational heterogeneity of the pore-lining TM2 helices, and shifted the lateral and radial tilting angles of TM2 toward a closed-channel conformation. The results differentiate two groups of systems based on the propofol binding symmetry. The difference between symmetric and asymmetric groups is correlated with the variance in the propofol-binding cavity adjacent to the hydrophobic gate and the force imposed by the bound propofol. Asymmetrically bound propofol produced greater variance in the cavity size that could further elevate the conformation heterogeneity. The force trajectory generated by propofol in each subunit over the course of a simulation exhibits an ellipsoidal shape, which has the larger component tangential to the pore. Asymmetric propofol binding creates an unbalanced force that expedites the channel conformation transitions. The findings from this study not only suggest that asymmetric binding underlies the propofol functional inhibition of GLIC, but also advocate for the role of symmetry breaking in facilitating channel conformational transitions.
Authors:
David Mowrey; Mary Hongying Cheng; Lu Tian Liu; Dan Willenbring; Xinghua Lu; Troy Wymore; Yan Xu; Pei Tang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-02-04
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  135     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-13     Completed Date:  2013-08-01     Revised Date:  2014-06-24    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2172-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Ligand-Gated Ion Channels / chemistry*
Ligands
Models, Molecular
Molecular Dynamics Simulation
Protein Conformation
Grant Support
ID/Acronym/Agency:
P41 RR006009/RR/NCRR NIH HHS; P41 RR06009/RR/NCRR NIH HHS; R01 GM056257/GM/NIGMS NIH HHS; R01 GM066358/GM/NIGMS NIH HHS; R01 LM010144/LM/NLM NIH HHS; R01 LM011155/LM/NLM NIH HHS; R01GM056257/GM/NIGMS NIH HHS; R01GM066358/GM/NIGMS NIH HHS; R37 GM049202/GM/NIGMS NIH HHS; R37GM049202/GM/NIGMS NIH HHS; T32 GM075770/GM/NIGMS NIH HHS; T32GM075770/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Ligand-Gated Ion Channels; 0/Ligands
Comments/Corrections

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