期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 38, 页码 15247-15252出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1210059109
关键词
alternative complex I; structural biology
资金
- National Institutes of Health [R01GM033712, R01EY020796]
- Exploratory Research for Advanced Technology Human Receptor Crystallography Project from the Japan Science
- Biotechnology and Biological Sciences Research Council [BB/G023425/1]
- Wellcome Trust at the Diamond Light Source Limited [062164/Z/00/Z]
- La Trobe Institute for Molecular Science
- BBSRC [BB/G023425/1, BB/D019311/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D019311/1, BB/G023425/1] Funding Source: researchfish
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.
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