Detailed Analysis of the Binding Mode of Vanilloids to Transient Receptor Potential Vanilloid Type I (TRPV1) by a Mutational and Computational Study.

Katsuya Ohbuchi,Masahiro Yamamoto,Takatsugu Hirokawa,Kazuo Ogawa,Eiji Warabi,Yoshikazu Mori,Andrej A Romanovsky

doi:10.1371/journal.pone.0162543

Katsuya Ohbuchi, Masahiro Yamamoto + Show 5 more

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https://doi.org/10.1371/journal.pone.0162543

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Abstract

Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel and a multimodal sensor protein. Since the precise structure of TRPV1 was obtained by electron cryo-microscopy, the binding mode of representative agonists such as capsaicin and resiniferatoxin (RTX) has been extensively characterized; however, detailed information on the binding mode of other vanilloids remains lacking. In this study, mutational analysis of human TRPV1 was performed, and four agonists (capsaicin, RTX, [6]-shogaol and [6]-gingerol) were used to identify amino acid residues involved in ligand binding and/or modulation of proton sensitivity. The detailed binding mode of each ligand was then simulated by computational analysis. As a result, three amino acids (L518, F591 and L670) were newly identified as being involved in ligand binding and/or modulation of proton sensitivity. In addition, in silico docking simulation and a subsequent mutational study suggested that [6]-gingerol might bind to and activate TRPV1 in a unique manner. These results provide novel insights into the binding mode of various vanilloids to the channel and will be helpful in developing a TRPV1 modulator.

Highlights

Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel and multimodal sensor protein [1,2]
We pinpointed 11 amino acid residues that are likely to be involved in ligand binding to human TRPV1 according to previous reports [10,18] and carried out a preliminary simulation analysis using the voltage-dependent potassium channel as a template structure
TRPV1 homology model enabled us to verify the results of our mutational study and provided insight into the various binding modes of the four vanilloids

Summary

Introduction

Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel and multimodal sensor protein [1,2]. TRPV1 is activated by noxious stimuli such as heat, protons, and various endogenous (e.g., anandamide or products of lipooxygenase) or exogenous (e.g., capsaicin or resiniferatoxin [RTX]) products [3]. TRPV1 is expressed in primary sensory neurons, where its activation results in the perception of pain; inhibition or desensitization of TRPV1 is thought to be a therapeutic strategy for neuropathic pain [2]. TRPV1 is expressed in non-neuronal cells or tissues such as the urinary bladder, PLOS ONE | DOI:10.1371/journal.pone.0162543. Binding Mode of Vanilloids in TRPV1 the ‘author contributions’ section. Tsumura & Co. was responsible for the study design, and the collection, analysis and interpretation of data

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