Membrane plasticity facilitates recognition of the inhibitor oligomycin by the mitochondrial ATP synthase rotor

Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):789-796. doi: 10.1016/j.bbabio.2018.03.019. Epub 2018 Apr 7.


Enzymes in the respiratory chain are increasingly seen as potential targets against multi-drug resistance of human pathogens and cancerous cells. However, a detailed understanding of the mechanism and specificity determinants of known inhibitors is still lacking. Oligomycin, for example, has been known to be an inhibitor of the membrane motor of the mitochondrial ATP synthase for over five decades, and yet little is known about its mode of action at the molecular level. In a recent breakthrough, a crystal structure of the S. cerevisiae c-subunit ring with bound oligomycin revealed the inhibitor docked on the outer face of the proton-binding sites, deep into the transmembrane region. However, the structure of the complex was obtained in an organic solvent rather than detergent or a lipid bilayer, and therefore it has been unclear whether this mode of recognition is physiologically relevant. Here, we use molecular dynamics simulations to address this question and gain insights into the mechanism of oligomycin inhibition. Our findings lead us to propose that oligomycin naturally partitions into the lipid/water interface, and that in this environment the inhibitor can indeed bind to any of the c-ring proton-carrying sites that are exposed to the membrane, thereby becoming an integral component of the proton-coordinating network. As the c-ring rotates within the membrane, driven either by downhill proton permeation or ATP hydrolysis, one of the protonated, oligomycin-bound sites eventually reaches the subunit-a interface and halts the rotary mechanism of the enzyme.

Keywords: Membrane bioenergetics; Membrane plasticity; Molecular simulation; Multi-drug resistance; Respiratory chain.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Binding Sites
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism*
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
  • Mitochondrial Proton-Translocating ATPases / chemistry
  • Mitochondrial Proton-Translocating ATPases / metabolism*
  • Molecular Dynamics Simulation
  • Oligomycins / chemistry
  • Oligomycins / metabolism*
  • Protein Conformation
  • Saccharomyces cerevisiae / enzymology*


  • Enzyme Inhibitors
  • Oligomycins
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases