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| {{STRUCTURE_2eg7| PDB=2eg7 | SCENE= }} | | {{STRUCTURE_2eg7| PDB=2eg7 | SCENE= }} |
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| '''The crystal structure of E. coli dihydroorotase complexed with HDDP'''
| | ===The crystal structure of E. coli dihydroorotase complexed with HDDP=== |
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| ==Overview==
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| Dihydroorotase (DHOase) catalyzes the reversible cyclization of N-carbamyl-L-aspartate (CA-asp) to L-dihydroorotate (DHO) in the de novo biosynthesis of pyrimidine nucleotides. DHOase is a potential anti-malarial drug target as malarial parasites can only synthesize pyrimidines via the de novo pathway and do not possess a salvage pathway. Here we report the structures of Escherichia coli DHOase crystallized without ligand (1.7 A resolution) and in the presence of the inhibitors 2-oxo-1,2,3,6-tetrahydropyrimidine-4,6-dicarboxylate (HDDP; 2.0 A) and 5-fluoroorotate (FOA, 2.2 A). These are the first crystal structures of DHOase-inhibitor complexes, providing structural information on the mode of inhibitor binding. HDDP possesses features of both the substrate and product, and ligates the Zn atoms in the active site. In addition, HDDP forms hydrogen bonds to the flexible loop (residues 105-115) stabilizing the "loop-in" conformation of the flexible loop normally associated with the presence of CA-asp in the active site. By contrast, FOA, a product-like inhibitor, binds to the active site in a similar fashion to DHO but does not ligate the Zn atoms directly nor stabilize the loop-in conformation. These structures define the necessary features for the future design of improved inhibitors of DHOase.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17550785}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17550785 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17550785}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Amidohydrolase]] | | [[Category: Amidohydrolase]] |
| [[Category: Tim barrel]] | | [[Category: Tim barrel]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 02:30:07 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 14:00:41 2008'' |
