1UUM

Rat dihydroorotate dehydrogenase (DHOD)in complex with atovaquone

Summary for 1UUM

• Entry DOI: 10.2210/pdb1uum/pdb
• Related: 1UUO
• Descriptor: DIHYDROOROTATE DEHYDROGENASE, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (6 entities in total)
• Functional Keywords: oxidoreductase, dihydroorotate dehydrogenase, brequinar, atovaquone, nucleotide metabolism, pyrimidine biosynthesis, fad, flavoprotein, transit peptide
• Biological source: RATTUS RATTUS (BLACK RAT, ROOF RAT)
• Total number of polymer chains: 2
• Total formula weight: 83225.05

Authors

Hansen, M.,Le Nours, J.,Johansson, E.,Antal, T.,Ullrich, A.,Loffler, M.,Larsen, S. (deposition date: 2004-01-06, release date: 2004-04-01, Last modification date: 2024-05-08)

Primary citation

Hansen, M.,Le Nours, J.,Johansson, E.,Antal, T.,Ullrich, A.,Loffler, M.,Larsen, S.
Inhibitor Binding in a Class 2 Dihydroorotate Dehydrogenase Causes Variations in the Membrane-Associated N-Terminal Domain
Protein Sci., 13:1031-, 2004

PubMed Abstract: The flavin enzyme dihydroorotate dehydrogenase (DHOD; EC 1.3.99.11) 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.

PubMed: 15044733
DOI: 10.1110/PS.03533004

Experimental method

X-RAY DIFFRACTION (2.3 Å)