2qcm
From Proteopedia
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| - | [[Image:2qcm.png|left|200px]] | ||
| - | + | ==Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 6-hydroxymethyl-UMP== | |
| + | <StructureSection load='2qcm' size='340' side='right'caption='[[2qcm]], [[Resolution|resolution]] 1.67Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <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> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.67Å</td></tr> | ||
| + | <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> | ||
| + | <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> | ||
| + | </table> | ||
| + | == 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/2qcm_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2qcm ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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. | ||
| - | + | 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> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 2qcm" style="background-color:#fffaf0;"></div> | |
| - | + | ||
==See Also== | ==See Also== | ||
| - | *[[Uridine 5'-monophosphate synthase|Uridine 5'-monophosphate synthase]] | + | *[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]] |
| - | + | == References == | |
| - | == | + | <references/> |
| - | < | + | __TOC__ |
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: Rudolph | + | [[Category: Rudolph M]] |
| - | [[Category: Wittmann | + | [[Category: Wittmann J]] |
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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
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