title: Mechanism of inhibition of the V-type molecular motor by tributyltin chloride.
abstract: Tributyltin chloride (TBT-Cl) is an endocrine disruptor found in many animal species, and it is also known to be an inhibitor for the V-ATPases that are emerging as potential targets in the treatment of diseases such as osteoporosis and cancer. We demonstrated by using biochemical and single-molecular imaging techniques that TBT-Cl arrests an elementary step for rotary catalysis of the V(1) motor domain. In the presence of TBT-Cl, the consecutive rotation of V(1) paused for a long duration ( approximately 0.5 s), even at saturated ATP concentrations, and the pausing positions were localized at 120 degrees intervals. Analysis of both the pausing time and moving time revealed that TBT-Cl has little effect on the binding affinity for ATP, but, rather, it arrests the catalytic event(s). This is the first report to demonstrate that an inhibitor arrests an elementary step for rotary catalysis of a V-type ATP-driven rotary motor.
authors.affiliation: Chemical Resources Laboratory, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Takeda
authors.forename: Chiyo
authors.initials: C
authors.lastname: Suno-Ikeda
authors.forename: Katsuya
authors.initials: K
authors.lastname: Shimabukuro
authors.forename: Masasuke
authors.initials: M
authors.lastname: Yoshida
authors.forename: Ken
authors.initials: K
authors.lastname: Yokoyama
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D052244:Endocrine Disruptors / Q000633:toxicity*; D007700:Kinetics; D009068:Movement; D017434:Protein Structure, Tertiary; D012399:Rotation; D016963:Thermus thermophilus / Q000201:enzymology*; D014220:Trialkyltin Compounds / Q000633:toxicity*; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D014220:Trialkyltin Compounds; C011559:tributyltin; D000255:Adenosine Triphosphate; D025262:Vacuolar Proton-Translocating ATPases