Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain.

  • Hansen M
  • Le Nours J
  • Johansson E
 et al. 
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The flavin enzyme dihydroorotate dehydrogenase (DHOD; EC catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis of UMP. The enzyme is a promising target for drug design in different biological and clinical applications for cancer and arthritis. The first crystal structure of the class 2 dihydroorotate dehydrogenase from rat has been determined in complex with its two inhibitors brequinar and atovaquone. These inhibitors have shown promising results as anti-proliferative, immunosuppressive, and antiparasitic agents. A unique feature of the class 2 DHODs is their N-terminal extension, which folds into a separate domain comprising two alpha-helices. This domain serves as the binding site for the two inhibitors and the respiratory quinones acting as the second substrate for the class 2 DHODs. The orientation of the first N-terminal helix is very different in the two complexes of rat DHOD (DHODR). Binding of atovaquone causes a 12 A movement of the first residue in the first alpha-helix. Based on the information from the two structures of DHODR, a model for binding of the quinone and the residues important for the interactions could be defined. His 56 and Arg 136, which are fully conserved in all class 2 DHODs, seem to play a key role in the interaction with the electron acceptor. The differences between the membrane-bound rat DHOD and membrane-associated class 2 DHODs exemplified by the Escherichia coli DHOD has been investigated by GRID computations of the hydrophobic probes predicted to interact with the membrane.

Author-supplied keywords

  • atovaquone
  • brequinar
  • centre for crystallographic studies
  • department of chemistry
  • dihydroorotate dehydrogenase
  • domain movement
  • inhibitor binding
  • membrane association
  • reprint requests to
  • sine larsen
  • universitetsparken
  • university of copenhagen

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  • Majbritt Hansen

  • Jérôme Le Nours

  • Eva Johansson

  • Torben Antal

  • Alexandra Ullrich

  • Monika Löffler

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