Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies

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

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)317-327
Number of pages11
JournalJournal of Computer-Aided Molecular Design
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2011
Externally publishedYes

Keywords

  • Capsaicin
  • Docking
  • Homology modeling
  • Mutation
  • Resiniferatoxin (RTX)
  • Transient receptor potential vanilloid type 1 (TRPV1)

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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    Lee, J. H., Lee, Y., Ryu, H., Kang, D. W., Lee, J., Lazar, J., Pearce, L. V., Pavlyukovets, V. A., Blumberg, P. M., & Choi, S. (2011). Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies. Journal of Computer-Aided Molecular Design, 25(4), 317-327. https://doi.org/10.1007/s10822-011-9421-5