2qcd: Difference between revisions
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<StructureSection load='2qcd' size='340' side='right'caption='[[2qcd]], [[Resolution|resolution]] 2.03Å' scene=''> | <StructureSection load='2qcd' size='340' side='right'caption='[[2qcd]], [[Resolution|resolution]] 2.03Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2qcd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[2qcd]] 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=2QCD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QCD FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.03Å</td></tr> | ||
<tr id=' | <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=U5P:URIDINE-5-MONOPHOSPHATE'>U5P</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=2qcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcd OCA], [https://pdbe.org/2qcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qcd RCSB], [https://www.ebi.ac.uk/pdbsum/2qcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qcd ProSAT]</span></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=2qcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcd OCA], [https://pdbe.org/2qcd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qcd RCSB], [https://www.ebi.ac.uk/pdbsum/2qcd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qcd ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == 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 == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qc/2qcd_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qc/2qcd_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/ | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Rudolph M]] | |||
[[Category: Rudolph | [[Category: Wittmann J]] | ||
[[Category: Wittmann | |||
Latest revision as of 11:32, 30 October 2024
Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to UMPCrystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase bound to UMP
Structural highlights
DiseaseUMPS_HUMAN Defects in UMPS are the cause of orotic aciduria type 1 (ORAC1) [MIM: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.[1] FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedUMP 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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