Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation.
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.
Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand.
Adam
A
Heikal
Yoshio
Y
Nakatani
Elyse
E
Dunn
Marion R
MR
Weimar
Catherine L
CL
Day
Edward N
EN
Baker
J Shaun
JS
Lott
Leonid A
LA
Sazanov
Gregory M
GM
Cook
D001407:Bacillus / Q000201:enzymology*; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004734:Energy Metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011809:Quinones / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D055672:Static Electricity
D008565:Membrane Proteins; D011809:Quinones; D009243:NAD; D005182:Flavin-Adenine Dinucleotide; C088908:NADH dehydrogenase II; D009245:NADH Dehydrogenase