The Structure of the Yeast NADH Dehydrogenase (Ndi1) Reveals Overlapping Binding Sites for Water- And Lipid-Soluble Substrates

Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15247-52. doi: 10.1073/pnas.1210059109. Epub 2012 Sep 4.

Abstract

Bioenergy is efficiently produced in the mitochondria by the respiratory system consisting of complexes I-V. In various organisms, complex I can be replaced by the alternative NADH-quinone oxidoreductase (NDH-2), which catalyzes the transfer of an electron from NADH via FAD to quinone, without proton pumping. The Ndi1 protein from Saccharomyces cerevisiae is a monotopic membrane protein, directed to the matrix. A number of studies have investigated the potential use of Ndi1 as a therapeutic agent against complex I disorders, and the NDH-2 enzymes have emerged as potential therapeutic targets for treatments against the causative agents of malaria and tuberculosis. Here we present the crystal structures of Ndi1 in its substrate-free, NAD(+)- and ubiquinone- (UQ2) complexed states. The structures reveal that Ndi1 is a peripheral membrane protein forming an intimate dimer, in which packing of the monomeric units within the dimer creates an amphiphilic membrane-anchor domain structure. Crucially, the structures of the Ndi1-NAD(+) and Ndi1-UQ2 complexes show overlapping binding sites for the NAD(+) and quinone substrates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray / methods
  • Cytoplasm / metabolism
  • Dimerization
  • Electron Transport Complex I / chemistry*
  • Electrons
  • Escherichia coli / metabolism
  • Lipids / chemistry*
  • Molecular Conformation
  • Mutation
  • Protein Structure, Tertiary
  • Protons
  • Quinones / chemistry
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Static Electricity
  • Water / chemistry

Substances

  • Lipids
  • Ndi1 protein, S cerevisiae
  • Protons
  • Quinones
  • Saccharomyces cerevisiae Proteins
  • Water
  • Electron Transport Complex I

Associated data

  • PDB/4G9K
  • PDB/4GAP
  • PDB/4GAV