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

TitleStructure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation.
Publication TypeJournal Article
Year of Publication2014
AuthorsHeikal, A, Nakatani, Y, Dunn, E, Weimar, MR, Day, CL, Baker, EN, J Lott, S, Sazanov, LA, Cook, GM
JournalMol Microbiol
Volume91
Issue5
Pagination950-64
Date Published2014 Mar
ISSN1365-2958
KeywordsBacillus, Binding Sites, Conserved Sequence, Crystallography, X-Ray, Energy Metabolism, Flavin-Adenine Dinucleotide, Membrane Proteins, Models, Molecular, NAD, NADH Dehydrogenase, Protein Multimerization, Protein Structure, Tertiary, Quinones, Saccharomyces cerevisiae, Static Electricity
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 2.5 Å 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.

DOI10.1111/mmi.12507
Alternate JournalMol. Microbiol.
Citation Key10.1111/mmi.12507
PubMed ID24444429
Grant ListMC_U105674180 / / Medical Research Council / United Kingdom