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[[Image:2qch.jpg|left|200px]]


{{Structure
==Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to 5-iodo-UMP==
|PDB= 2qch |SIZE=350|CAPTION= <scene name='initialview01'>2qch</scene>, resolution 1.95&Aring;
<StructureSection load='2qch' size='340' side='right'caption='[[2qch]], [[Resolution|resolution]] 1.95&Aring;' 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>
== Structural highlights ==
|LIGAND= <scene name='pdbligand=5IU:5-IODO-2&#39;-DEOXYURIDINE-5&#39;-MONOPHOSPHATE'>5IU</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=UMP:2&#39;-DEOXYURIDINE+5&#39;-MONOPHOSPHATE'>UMP</scene>
<table><tr><td colspan='2'>[[2qch]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QCH FirstGlance]. <br>
|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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
|GENE= UMPS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5IU:5-IODO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>5IU</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2qch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qch OCA], [https://pdbe.org/2qch PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qch RCSB], [https://www.ebi.ac.uk/pdbsum/2qch PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qch ProSAT]</span></td></tr>
|RELATEDENTRY=[[2v30|2v30]], [[2jgy|2jgy]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qch OCA], [http://www.ebi.ac.uk/pdbsum/2qch PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qch RCSB]</span>
== Disease ==
}}
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN] Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM:[https://omim.org/entry/258900 258900]. A disorder of pyrimidine metabolism resulting in megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. A minority of cases have additional features, particularly congenital malformations and immune deficiencies.<ref>PMID:9042911</ref>
== Function ==
[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN]
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qc/2qch_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2qch ConSurf].
<div style="clear:both"></div>


'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to 5-iodo-UMP'''
==See Also==
 
*[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]]
 
== References ==
==Overview==
<references/>
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.
__TOC__
 
</StructureSection>
==Disease==
Known disease associated with this structure: Oroticaciduria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=258900 258900]]
 
==About this Structure==
2QCH is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCH 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:[http://www.ncbi.nlm.nih.gov/pubmed/18184586 18184586]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Orotidine-5'-phosphate decarboxylase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Rudolph M]]
[[Category: Rudolph, M.]]
[[Category: Wittmann J]]
[[Category: Wittmann, J.]]
[[Category: catalytic proficiency]]
[[Category: decarboxylase]]
[[Category: lyase]]
[[Category: ump synthase]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:47:38 2008''
Retrieved from "https://proteopedia.org/2qch"