2EG7

The crystal structure of E. coli dihydroorotase complexed with HDDP

Summary for 2EG7

• Entry DOI: 10.2210/pdb2eg7/pdb
• Related: 1XGE 2EG6 2EG8
• Descriptor: Dihydroorotase, ZINC ION, 2-OXO-1,2,3,6-TETRAHYDROPYRIMIDINE-4,6-DICARBOXYLIC ACID, ... (4 entities in total)
• Functional Keywords: amidohydrolase, tim barrel, hydrolase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 78176.04

Authors

Lee, M.,Maher, M.J.,Guss, J.M. (deposition date: 2007-02-28, release date: 2007-07-03, Last modification date: 2023-11-15)

Primary citation

Lee, M.,Chan, C.W.,Graham, S.C.,Christopherson, R.I.,Guss, J.M.,Maher, M.J.
Structures of Ligand-free and Inhibitor Complexes of Dihydroorotase from Escherichia coli: Implications for Loop Movement in Inhibitor Design
J.Mol.Biol., 370:812-825, 2007

PubMed Abstract: 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.

PubMed: 17550785
DOI: 10.1016/j.jmb.2007.05.019

Experimental method

X-RAY DIFFRACTION (2 Å)