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Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):E137-45. doi: 10.1073/pnas.1517288113. Epub 2015 Dec 30.

Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin.

Author information

1
Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122; Department of Chemistry, Temple University, Philadelphia, PA 19122; Department of Pharmaceutical Chemistry, Tanta University, 31527 Tanta, Egypt;
2
Department of Pharmacology, Physiology and Neuroscience, Rutgers-New Jersey Medical School, Newark, NJ 07103.
3
Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122;
4
Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122; Department of Chemistry, Temple University, Philadelphia, PA 19122; mlklein@temple.edu vincenzo.carnevale@temple.edu.
5
Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122; mlklein@temple.edu vincenzo.carnevale@temple.edu.

Abstract

The transient receptor potential cation channel subfamily V member 1 (TRPV1) or vanilloid receptor 1 is a nonselective cation channel that is involved in the detection and transduction of nociceptive stimuli. Inflammation and nerve damage result in the up-regulation of TRPV1 transcription, and, therefore, modulators of TRPV1 channels are potentially useful in the treatment of inflammatory and neuropathic pain. Understanding the binding modes of known ligands would significantly contribute to the success of TRPV1 modulator drug design programs. The recent cryo-electron microscopy structure of TRPV1 only provides a coarse characterization of the location of capsaicin (CAPS) and resiniferatoxin (RTX). Herein, we use the information contained in the experimental electron density maps to accurately determine the binding mode of CAPS and RTX and experimentally validate the computational results by mutagenesis. On the basis of these results, we perform a detailed analysis of TRPV1-ligand interactions, characterizing the protein ligand contacts and the role of individual water molecules. Importantly, our results provide a rational explanation and suggestion of TRPV1 ligand modifications that should improve binding affinity.

KEYWORDS:

docking; heat-sensitive; ligand-gated; nociception; vanilloid

PMID:
26719417
PMCID:
PMC4720335
DOI:
10.1073/pnas.1517288113
[Indexed for MEDLINE]
Free PMC Article

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