title: The structure of the yeast NADH dehydrogenase (Ndi1) reveals overlapping binding sites for water- and lipid-soluble substrates.
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.
authors.affiliation: Division of Molecular Biosciences, Imperial College, London, United Kingdom.
authors.forename: Momi
authors.initials: M
authors.lastname: Iwata
authors.forename: Yang
authors.initials: Y
authors.lastname: Lee
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yamashita
authors.forename: Takao
authors.initials: T
authors.lastname: Yagi
authors.forename: So
authors.initials: S
authors.lastname: Iwata
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Cameron
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Maher
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray / Q000379:methods; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D042967:Electron Transport Complex I / Q000737:chemistry*; D004583:Electrons; D004926:Escherichia coli / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008968:Molecular Conformation; D009154:Mutation; D017434:Protein Structure, Tertiary; D011522:Protons; D011809:Quinones / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D055672:Static Electricity; D014867:Water / Q000737:chemistry
chemical_list: D008055:Lipids; C493237:Ndi1 protein, S cerevisiae; D011522:Protons; D011809:Quinones; D029701:Saccharomyces cerevisiae Proteins; D014867:Water; D042967:Electron Transport Complex I