Reference - Detail
|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.|
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, -shogaol and -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 -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.
|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*|
|WOS Category||BIOCHEMISTRY & MOLECULAR BIOLOGY|
|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).|