Journal of Computer-Aided Molecular Design

, Volume 25, Issue 4, pp 317–327 | Cite as

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
Article

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.

Keywords

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

Notes

Acknowledgments

This research was supported by Grants R01-2007-000-20052-0 from the Ministry of Education, Science and Technology (MEST) and National Research Foundation of Korea (NRF) (to J. Lee and S. Choi), the National Core Research Center (NCRC) program (R15-2006-020) of MEST and NRF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University (to S. Choi), and the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (to P. M. Blumberg).

Supplementary material

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Supplementary material 1 (DOC 4813 kb)

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Jin Hee Lee
    • 1
    • 2
  • Yoonji Lee
    • 1
    • 2
  • HyungChul Ryu
    • 3
  • Dong Wook Kang
    • 3
  • Jeewoo Lee
    • 3
  • Jozsef Lazar
    • 4
  • Larry V. Pearce
    • 4
  • Vladimir A. Pavlyukovets
    • 4
  • Peter M. Blumberg
    • 4
  • Sun Choi
    • 1
    • 2
  1. 1.College of Pharmacy, Division of Life and Pharmaceutical SciencesEwha Womans UniversitySeoulKorea
  2. 2.National Core Research Center for Cell Signaling and Drug Discovery ResearchEwha Womans UniversitySeoulKorea
  3. 3.Research Institute of Pharmaceutical Sciences, College of PharmacySeoul National UniversitySeoulKorea
  4. 4.Laboratory of Cancer Biology and Genetics, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA

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