2qcm

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[[Image:2qcm.jpg|left|200px]]
 
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{{Structure
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==Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 6-hydroxymethyl-UMP==
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|PDB= 2qcm |SIZE=350|CAPTION= <scene name='initialview01'>2qcm</scene>, resolution 1.67&Aring;
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<StructureSection load='2qcm' size='340' side='right'caption='[[2qcm]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
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|SITE= <scene name='pdbsite=AC1:Jw5+Binding+Site+For+Residue+A+482'>AC1</scene>
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=JW5:6-(HYDROXYMETHYL)URIDINE+5&#39;-(DIHYDROGEN+PHOSPHATE)'>JW5</scene>, <scene name='pdbligand=S:SULFUR+ATOM'>S</scene>
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<table><tr><td colspan='2'>[[2qcm]] is a 1 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=2QCM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QCM FirstGlance]. <br>
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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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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.67&#8491;</td></tr>
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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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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSS:S-MERCAPTOCYSTEINE'>CSS</scene>, <scene name='pdbligand=JW5:6-(HYDROXYMETHYL)URIDINE+5-(DIHYDROGEN+PHOSPHATE)'>JW5</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2qcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcm OCA], [https://pdbe.org/2qcm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qcm RCSB], [https://www.ebi.ac.uk/pdbsum/2qcm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qcm ProSAT]</span></td></tr>
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|RELATEDENTRY=[[2v30|2v30]], [[2jgy|2jgy]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcm OCA], [http://www.ebi.ac.uk/pdbsum/2qcm PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qcm RCSB]</span>
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== Disease ==
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}}
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[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>
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== Function ==
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'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 6-hydroxymethyl-UMP'''
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[https://www.uniprot.org/uniprot/UMPS_HUMAN UMPS_HUMAN]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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==Overview==
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qc/2qcm_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2qcm ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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.
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.
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==Disease==
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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<ref>PMID:18184586</ref>
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Known disease associated with this structure: Oroticaciduria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=258900 258900]]
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2QCM 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=2QCM OCA].
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</div>
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<div class="pdbe-citations 2qcm" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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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]
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*[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Orotidine-5'-phosphate decarboxylase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Rudolph M]]
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[[Category: Rudolph, M.]]
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[[Category: Wittmann J]]
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[[Category: Wittmann, J.]]
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[[Category: catalytic proficiency]]
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[[Category: decarboxylase]]
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[[Category: lyase]]
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[[Category: ump synthase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:47:41 2008''
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Current revision

Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 6-hydroxymethyl-UMP

PDB ID 2qcm

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