2qcn
|
Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP
OverviewOverview
UMP synthase (UMPS) catalyzes the last two steps of de novo pyrimidine, nucleotide synthesis and is a potential cancer drug target. The C-terminal, domain of UMPS is orotidine-5'-monophosphate decarboxylase (OMPD), a, cofactor-less yet extremely efficient enzyme. Studies of OMPDs from, micro-organisms led to the proposal of several noncovalent decarboxylation, mechanisms via high-energy intermediates. We describe nine crystal, structures of human OMPD in complex with substrate, product, and, nucleotide inhibitors. Unexpectedly, simple compounds can replace the, natural nucleotides and induce a closed conformation of OMPD, defining a, tripartite catalytic site. The structures outline the requirements drugs, must meet to maximize therapeutic effects and minimize cross-species, activity. Chemical mimicry by iodide identified a CO(2) product binding, site. Plasticity of catalytic residues and a covalent OMPD-UMP complex, prompt a reevaluation of the prevailing decarboxylation mechanism in favor, of covalent intermediates. This mechanism can also explain the observed, catalytic promiscuity of OMPD.
About this StructureAbout this Structure
2QCN is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Full crystallographic information is available from OCA.
ReferenceReference
Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design., Wittmann JG, Heinrich D, Gasow K, Frey A, Diederichsen U, Rudolph MG, Structure. 2008 Jan;16(1):82-92. PMID:18184586
Page seeded by OCA on Wed Jan 23 10:43:39 2008