Ubiquinone binding site of yeast NADH dehydrogenase revealed by structures binding novel competitive- and mixed-type inhibitors

  • 三芳, 秀人
    Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University
  • 岩田, 想
    Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo・School of Tropical Medicine and Global Health, Nagasaki University
  • Shiba, Tomoo
    Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology
  • Oohashi, Takumi
    Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo
  • Iwata, So
    Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College・Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus・Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Human Receptor Crystallography Project・Department of Cell Biology, Graduate School of Medicine, Kyoto University・Systems and Structural Biology Centre, RIKEN
  • Yagi, Takao
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla
  • Kosaka, Hiroaki
    Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University・Osaka Jikei College
  • Miyoshi, Hideto
    Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University
  • Harada, Shigeharu
    Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology
  • Kita, Kiyoshi
    Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo・School of Tropical Medicine and Global Health, Nagasaki University
  • Hirano, Katsuya
    Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University

抄録

Yeast Ndi1 is a monotopic alternative NADH dehydrogenase. Its crystal structure in complex with the electron acceptor, ubiquinone, has been determined. However, there has been controversy regarding the ubiquinone binding site. To address these points, we identified the first competitive inhibitor of Ndi1, stigmatellin, along with new mixed-type inhibitors, AC0-12 and myxothiazol, and thereby determined the crystal structures of Ndi1 in complexes with the inhibitors. Two separate binding sites of stigmatellin, STG-1 and STG-2, were observed. The electron density at STG-1, located at the vicinity of the FAD cofactor, further demonstrated two binding modes: STG-1a and STG-1b. AC0-12 and myxothiazol are also located at the vicinity of FAD. The comparison of the binding modes among stigmatellin at STG-1, AC0-12, and myxothiazol revealed a unique position for the aliphatic tail of stigmatellin at STG-1a. Mutations of amino acid residues that interact with this aliphatic tail at STG-1a reduced the affinity of Ndi1 for ubiquinone. In conclusion, the position of the aliphatic tail of stigmatellin at STG-1a provides a structural basis for its competitive inhibition of Ndi1. The inherent binding site of ubiquinone is suggested to overlap with STG-1a that is distinct from the binding site for NADH.

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