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, [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.
Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan.
Katsuya
http://orcid.org/0000-0001-6756-3260
K
Ohbuchi
Analytical and Pharmaceutical Technology Research Center, Tsumura and Co., Ibaraki, Japan.
Yoshikazu
Y
Mori
Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan.
Kazuo
K
Ogawa
Environmental Molecular Biology Laboratory, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
Eiji
E
Warabi
Tsumura Research Laboratories, Tsumura and Co., Ibaraki, Japan.
Masahiro
M
Yamamoto
Molecular Profiling Research Center for Drug Discovery, AIST, Koto-ku, Tokyo, Japan.|Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
Takatsugu
T
Hirokawa
D000596:Amino Acids / Q000737:chemistry; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000737:chemistry / Q000494:pharmacology; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology; D004252:DNA Mutational Analysis; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D005233:Fatty Alcohols / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D011522:Protons; D015203:Reproducibility of Results; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000819:agonists* / Q000737:chemistry / Q000235:genetics*
D000596:Amino Acids; D002396:Catechols; D004224:Diterpenes; D005233:Fatty Alcohols; D008024:Ligands; D050505:Mutant Proteins; D011522:Protons; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C040115:shogaol; C007845:gingerol; C024353:resiniferatoxin; D002211:Capsaicin; D002118:Calcium