RRC ID 47635
Author Ohbuchi K, Mori Y, Ogawa K, Warabi E, Yamamoto M, Hirokawa T.
Title Detailed Analysis of the Binding Mode of Vanilloids to Transient Receptor Potential Vanilloid Type I (TRPV1) by a Mutational and Computational Study.
Journal PLoS One
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.
Volume 11(9)
Pages e0162543
Published 2016-1-1
DOI 10.1371/journal.pone.0162543
PII PONE-D-16-20075
PMID 27606946
PMC PMC5015962
MeSH Amino Acids / chemistry Calcium / metabolism Capsaicin / chemistry Capsaicin / pharmacology Catechols / chemistry Catechols / pharmacology DNA Mutational Analysis Diterpenes / chemistry Diterpenes / pharmacology Fatty Alcohols / chemistry Fatty Alcohols / pharmacology Humans Kinetics Ligands Models, Molecular* Molecular Docking Simulation Mutant Proteins / chemistry Mutant Proteins / metabolism Mutation / genetics* Point Mutation / genetics Protons Reproducibility of Results Sequence Homology, Amino Acid Structure-Activity Relationship TRPV Cation Channels / agonists* TRPV Cation Channels / chemistry TRPV Cation Channels / genetics*
IF 2.74
Times Cited 9
DNA material pcDNA3.1-hTRPV1-FLAG WT (RDB14587) pcDNA3.1-hTRPV1-FLAG-C158A (RDB14588) pcDNA3.1-hTRPV1-FLAG-L515A (RDB14589) pcDNA3.1-hTRPV1-FLAG-L518A (RDB14590) pcDNA3.1-hTRPV1-FLAG-L547A (RDB14591) pcDNA3.1-hTRPV1-FLAG-T550A (RDB14592) pcDNA3.1-hTRPV1-FLAG-I573A (RDB14593) pcDNA3.1-hTRPV1-FLAG-F587A (RDB14594) pcDNA3.1-hTRPV1-FLAG-F591A (RDB14595) pcDNA3.1-hTRPV1-FLAG-L670A (RDB14596) pcDNA3.1-hTRPV1-FLAG-S512A (RDB14597) pcDNA3.1-hTRPV1-FLAG-Y511F (RDB14598).