2QCL
Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to OMP
Summary for 2QCL
| Entry DOI | 10.2210/pdb2qcl/pdb |
| Related | 2jgy 2v30 |
| Descriptor | Uridine 5'-monophosphate synthase (UMP synthase), OROTIDINE-5'-MONOPHOSPHATE, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | ump synthase, decarboxylase, catalytic proficiency, lyase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 57425.99 |
| Authors | Wittmann, J.,Rudolph, M. (deposition date: 2007-06-19, release date: 2007-11-06, Last modification date: 2024-02-21) |
| Primary citation | Wittmann, J.G.,Heinrich, D.,Gasow, K.,Frey, A.,Diederichsen, U.,Rudolph, M.G. Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design. Structure, 16:82-92, 2008 Cited by PubMed Abstract: 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. PubMed: 18184586DOI: 10.1016/j.str.2007.10.020 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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