Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation Journal Article


Author(s): Heikal, Adam ; Nakatani, Yoshio; Dunn, Elyse A; Weimar, Marion R; Day, Catherine; Baker, Edward N; Lott, Shaun J; Sazanov, Leonid A; Cook, Gregory
Article Title: Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation
Affiliation
Abstract: Non-proton pumping type II NADH dehydrogenase (NDH-2) plays a central role in the respiratory metabolism of bacteria, and in the mitochondria of fungi, plants and protists. The lack of NDH-2 in mammalian mitochondria and its essentiality in important bacterial pathogens suggests these enzymes may represent a potential new drug target to combat microbial pathogens. Here, we report the first crystal structure of a bacterial NDH-2 enzyme at 2.5Å resolution from Caldalkalibacillus thermarum. The NDH-2 structure reveals a homodimeric organization that has a unique dimer interface. NDH-2 is localized to the cytoplasmic membrane by two separated C-terminal membrane-anchoring regions that are essential for membrane localization and FAD binding, but not NDH-2 dimerization. Comparison of bacterial NDH-2 with the yeast NADH dehydrogenase (Ndi1) structure revealed non-overlapping binding sites for quinone and NADH in the bacterial enzyme. The bacterial NDH-2 structure establishes a framework for the structure-based design of small-molecule inhibitors.
Keywords: membrane protein; unclassified drug; bacterial enzyme; flavine adenine nucleotide; fungal enzyme; homodimer; quinone derivative; reduced nicotinamide adenine dinucleotide; reduced nicotinamide adenine dinucleotide dehydrogenase; type II NADH dehydrogenase
Journal Title: Molecular Microbiology
Volume: 91
Issue 5
ISSN: 1365-2958
Publisher: Wiley-Blackwell  
Date Published: 2014-03-01
Start Page: 950
End Page: 964
Sponsor: Funded by Health Research Council of New Zealand Royal Society of New Zealand University of Otago New Zealand Synchrotron Group
DOI: 10.1111/mmi.12507
Open access: no