2qcd

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[[Image:2qcd.jpg|left|200px]]
[[Image:2qcd.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2qcd |SIZE=350|CAPTION= <scene name='initialview01'>2qcd</scene>, resolution 2.03&Aring;
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The line below this paragraph, containing "STRUCTURE_2qcd", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:U5p+Binding+Site+For+Residue+A+1'>AC1</scene>, <scene name='pdbsite=AC2:U5p+Binding+Site+For+Residue+B+2'>AC2</scene> and <scene name='pdbsite=AC3:S+Binding+Site+For+Residue+A+481'>AC3</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=S:SULFUR+ATOM'>S</scene>, <scene name='pdbligand=U5P:URIDINE-5&#39;-MONOPHOSPHATE'>U5P</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE= UMPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2qcd| PDB=2qcd | SCENE= }}
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|RELATEDENTRY=[[2qcc|2QCC]], [[2v30|2v30]], [[2jgy|2jgy]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcd OCA], [http://www.ebi.ac.uk/pdbsum/2qcd PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qcd RCSB]</span>
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}}
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'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to UMP'''
'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to UMP'''
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[[Category: Rudolph, M.]]
[[Category: Rudolph, M.]]
[[Category: Wittmann, J.]]
[[Category: Wittmann, J.]]
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[[Category: catalytic proficiency]]
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[[Category: Catalytic proficiency]]
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[[Category: decarboxylase]]
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[[Category: Decarboxylase]]
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[[Category: lyase]]
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[[Category: Lyase]]
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[[Category: ump synthase]]
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[[Category: Ump synthase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 14:43:13 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:47:34 2008''
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Revision as of 11:43, 4 May 2008

Image:2qcd.jpg

Template:STRUCTURE 2qcd

Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to 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

2QCD 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 May 4 14:43:13 2008

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OCA

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