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| {{STRUCTURE_1uum| PDB=1uum | SCENE= }} | | {{STRUCTURE_1uum| PDB=1uum | SCENE= }} |
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| '''RAT DIHYDROOROTATE DEHYDROGENASE (DHOD)IN COMPLEX WITH ATOVAQUONE'''
| | ===RAT DIHYDROOROTATE DEHYDROGENASE (DHOD)IN COMPLEX WITH ATOVAQUONE=== |
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| ==Overview==
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| 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. | | The line below this paragraph, {{ABSTRACT_PUBMED_15044733}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15044733 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15044733}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Pyrimidine biosynthesis]] | | [[Category: Pyrimidine biosynthesis]] |
| [[Category: Transit peptide]] | | [[Category: Transit peptide]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 11:42:55 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 05:14:21 2008'' |
