PMID:15044733
| Citation |
Hansen, M, Le Nours, J, Johansson, E, Antal, T, Ullrich, A, Löffler, M and Larsen, S (2004) Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain. Protein Sci. 13:1031-42 |
|---|---|
| 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. |
| Links |
PubMed PMC2280058 Online version:10.1110/ps.03533004 |
| Keywords |
Amino Acid Sequence; Aniline Compounds/chemistry; Aniline Compounds/metabolism; Animals; Atovaquone; Biphenyl Compounds/chemistry; Biphenyl Compounds/metabolism; Catalysis; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Hydrogen Bonding; Hydroxybutyrates/chemistry; Hydroxybutyrates/metabolism; Immunosuppressive Agents/chemistry; Immunosuppressive Agents/metabolism; Models, Molecular; Molecular Sequence Data; Molecular Structure; Naphthoquinones/chemistry; Naphthoquinones/metabolism; Orotic Acid/analogs & derivatives; Orotic Acid/chemistry; Oxidoreductases Acting on CH-CH Group Donors/chemistry; Oxidoreductases Acting on CH-CH Group Donors/metabolism; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Rats; Sequence Alignment; Substrate Specificity |
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