Mechanism of inhibition of the V-type molecular motor by tributyltin chloride

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Mizuho Takeda1, Chiyo Suno-Ikeda, Katsuya Shimabukuro

  • 1Chemical Resources Laboratory, Tokyo Institute of Technology, Yokohama, Japan.

Biophysical Journal
|February 3, 2009
PubMed

Insights

Tributyltin chloride (TBT-Cl) inhibits V-ATPases, crucial for cellular energy. This study shows TBT-Cl halts V(1) motor rotation at specific steps, offering insights into V-ATPase function and potential drug development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biophysics

Background:

  • Tributyltin chloride (TBT-Cl) is a known endocrine disruptor.
  • V-ATPases are implicated as therapeutic targets for osteoporosis and cancer.
  • V-ATPases function as rotary motors essential for cellular processes.

Purpose of the Study:

  • To investigate the inhibitory mechanism of TBT-Cl on V-ATPases.
  • To elucidate the effect of TBT-Cl on the rotary catalysis of the V(1) motor domain.

Main Methods:

  • Biochemical assays
  • Single-molecular imaging techniques
  • Analysis of rotary motor kinetics

Main Results:

  • TBT-Cl arrests an elementary step in the rotary catalysis of the V(1) motor domain.
  • Rotation pauses occurred at 120-degree intervals with a duration of approximately 0.5 seconds.
  • TBT-Cl affects the catalytic step rather than ATP binding affinity.

Conclusions:

  • This is the first demonstration of an inhibitor arresting an elementary step in V-type ATP-driven rotary motor catalysis.
  • TBT-Cl's mechanism provides a novel understanding of V-ATPase inhibition.
  • Findings may inform the development of targeted therapies for diseases involving V-ATPases.

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