Document Detail

Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies.
MedLine Citation:
PMID:  21448716     Owner:  NLM     Status:  MEDLINE    
The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.
Jin Hee Lee; Yoonji Lee; HyungChul Ryu; Dong Wook Kang; Jeewoo Lee; Jozsef Lazar; Larry V Pearce; Vladimir A Pavlyukovets; Peter M Blumberg; Sun Choi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2011-03-30
Journal Detail:
Title:  Journal of computer-aided molecular design     Volume:  25     ISSN:  1573-4951     ISO Abbreviation:  J. Comput. Aided Mol. Des.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-05-13     Completed Date:  2011-08-26     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8710425     Medline TA:  J Comput Aided Mol Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  317-27     Citation Subset:  IM    
College of Pharmacy, Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
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MeSH Terms
Amino Acid Sequence
Analgesics / chemistry*,  pharmacology
CHO Cells
Capsaicin / chemistry*,  pharmacology
DNA Mutational Analysis
Diterpenes / chemistry*,  pharmacology
Models, Molecular*
Molecular Sequence Data
Pain Management
Protein Conformation
TRPV Cation Channels / agonists*,  chemistry*,  genetics
Grant Support
Z01 BC005270-27/BC/NCI NIH HHS; ZIA BC005270-28/BC/NCI NIH HHS
Reg. No./Substance:
0/Analgesics; 0/Diterpenes; 0/Ligands; 0/TRPV Cation Channels; 0/Trpv1 protein, rat; 404-86-4/Capsaicin; A5O6P1UL4I/resiniferatoxin

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