Structure of the Bacterial Type II NADH Dehydrogenase: A Monotopic Membrane Protein With an Essential Role in Energy Generation

Mol Microbiol. 2014 Mar;91(5):950-64. doi: 10.1111/mmi.12507. Epub 2014 Jan 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacillus / enzymology*
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • Energy Metabolism*
  • Flavin-Adenine Dinucleotide / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / isolation & purification
  • Membrane Proteins / metabolism
  • Models, Molecular
  • NAD / metabolism
  • NADH Dehydrogenase / chemistry*
  • NADH Dehydrogenase / isolation & purification
  • NADH Dehydrogenase / metabolism
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Quinones / metabolism
  • Saccharomyces cerevisiae / enzymology
  • Static Electricity

Substances

  • Membrane Proteins
  • Quinones
  • NAD
  • Flavin-Adenine Dinucleotide
  • NADH dehydrogenase II
  • NADH Dehydrogenase

Associated data

  • PDB/4NWZ