Journal article

Structures of ligand-free and inhibitor complexes of Dihydroorotase from Escherichia coli: Implications for loop movement in inhibitor design

Mihwa Lee, Camilla W Chan, Stephen C Graham, Richard I Christopherson, J Mitchell Guss, Megan J Maher

JOURNAL OF MOLECULAR BIOLOGY | ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD | Published : 2007

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 o..

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University of Melbourne Researchers