2qch
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2qch |SIZE=350|CAPTION= <scene name='initialview01'>2qch</scene>, resolution 1.95Å | |PDB= 2qch |SIZE=350|CAPTION= <scene name='initialview01'>2qch</scene>, resolution 1.95Å | ||
|SITE= <scene name='pdbsite=AC1:Iod+Binding+Site+For+Residue+A+5'>AC1</scene>, <scene name='pdbsite=AC2:Iod+Binding+Site+For+Residue+B+6'>AC2</scene>, <scene name='pdbsite=AC3:5iu+Binding+Site+For+Residue+A+1'>AC3</scene>, <scene name='pdbsite=AC4:Ump+Binding+Site+For+Residue+A+2'>AC4</scene>, <scene name='pdbsite=AC5:5iu+Binding+Site+For+Residue+B+3'>AC5</scene> and <scene name='pdbsite=AC6:Ump+Binding+Site+For+Residue+B+4'>AC6</scene> | |SITE= <scene name='pdbsite=AC1:Iod+Binding+Site+For+Residue+A+5'>AC1</scene>, <scene name='pdbsite=AC2:Iod+Binding+Site+For+Residue+B+6'>AC2</scene>, <scene name='pdbsite=AC3:5iu+Binding+Site+For+Residue+A+1'>AC3</scene>, <scene name='pdbsite=AC4:Ump+Binding+Site+For+Residue+A+2'>AC4</scene>, <scene name='pdbsite=AC5:5iu+Binding+Site+For+Residue+B+3'>AC5</scene> and <scene name='pdbsite=AC6:Ump+Binding+Site+For+Residue+B+4'>AC6</scene> | ||
| - | |LIGAND= <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=5IU:5-IODO-2 | + | |LIGAND= <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=5IU:5-IODO-2'-DEOXYURIDINE-5'-MONOPHOSPHATE'>5IU</scene> and <scene name='pdbligand=UMP:2'-DEOXYURIDINE 5'-MONOPHOSPHATE'>UMP</scene> |
|ACTIVITY= [http://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] | |ACTIVITY= [http://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] | ||
|GENE= UMPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= UMPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
| Line 36: | Line 36: | ||
[[Category: ump synthase]] | [[Category: ump synthase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 15:44:06 2008'' |
Revision as of 13:44, 23 March 2008
| |||||||
| , resolution 1.95Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | , , , , and | ||||||
| Ligands: | , and | ||||||
| Gene: | UMPS (Homo sapiens) | ||||||
| Activity: | Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to 5-iodo-UMP
Contents |
Overview
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.
Disease
Known disease associated with this structure: Oroticaciduria OMIM:[258900]
About this Structure
2QCH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Sun Mar 23 15:44:06 2008
