This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.


2qcn

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
(New page: 200px<br /><applet load="2qcn" size="350" color="white" frame="true" align="right" spinBox="true" caption="2qcn, resolution 1.85&Aring;" /> '''Covalent complex of ...)
Current revision (08:15, 25 June 2021) (edit) (undo)
 
(15 intermediate revisions not shown.)
Line 1: Line 1:
-
[[Image:2qcn.jpg|left|200px]]<br /><applet load="2qcn" size="350" color="white" frame="true" align="right" spinBox="true"
 
-
caption="2qcn, resolution 1.85&Aring;" />
 
-
'''Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP'''<br />
 
-
==Overview==
+
==Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP==
-
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.
+
<StructureSection load='2qcn' size='340' side='right'caption='[[2qcn]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[2qcn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QCN FirstGlance]. <br>
 +
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=U5P:URIDINE-5-MONOPHOSPHATE'>U5P</scene></td></tr>
 +
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2qcc|2qcc]], [[2qcd|2qcd]], [[2qce|2qce]], [[2qcf|2qcf]], [[2qcg|2qcg]], [[2qch|2qch]], [[2qcl|2qcl]], [[2qcm|2qcm]], [[2v30|2v30]], [[2jgy|2jgy]]</div></td></tr>
 +
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UMPS ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 +
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Orotidine-5'-phosphate_decarboxylase Orotidine-5'-phosphate decarboxylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.1.1.23 4.1.1.23] </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=2qcn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qcn OCA], [https://pdbe.org/2qcn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qcn RCSB], [https://www.ebi.ac.uk/pdbsum/2qcn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qcn 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>
 +
== 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/2qcn_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=2qcn 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.
-
==About this Structure==
+
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>
-
2QCN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=U5P:'>U5P</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCN OCA].
+
-
==Reference==
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
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://ispc.weizmann.ac.il//pmbin/getpm?pmid=18184586 18184586]
+
</div>
-
[[Category: Homo sapiens]]
+
<div class="pdbe-citations 2qcn" style="background-color:#fffaf0;"></div>
-
[[Category: Orotidine-5'-phosphate decarboxylase]]
+
-
[[Category: Single protein]]
+
-
[[Category: Rudolph, M.]]
+
-
[[Category: Wittmann, J.]]
+
-
[[Category: GOL]]
+
-
[[Category: SO4]]
+
-
[[Category: U5P]]
+
-
[[Category: alternative splicing]]
+
-
[[Category: catalytic proficiency]]
+
-
[[Category: decarboxylase]]
+
-
[[Category: disease mutation]]
+
-
[[Category: glycosyltransferase]]
+
-
[[Category: lyase]]
+
-
[[Category: multifunctional enzyme]]
+
-
[[Category: polymorphism]]
+
-
[[Category: pyrimidine biosynthesis]]
+
-
[[Category: transferase]]
+
-
[[Category: ump synthase]]
+
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 10:43:39 2008''
+
==See Also==
 +
*[[Phosphoribosyltransferase 3D structures|Phosphoribosyltransferase 3D structures]]
 +
*[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]]
 +
== References ==
 +
<references/>
 +
__TOC__
 +
</StructureSection>
 +
[[Category: Human]]
 +
[[Category: Large Structures]]
 +
[[Category: Orotidine-5'-phosphate decarboxylase]]
 +
[[Category: Rudolph, M]]
 +
[[Category: Wittmann, J]]
 +
[[Category: Catalytic proficiency]]
 +
[[Category: Decarboxylase]]
 +
[[Category: Disease mutation]]
 +
[[Category: Glycosyltransferase]]
 +
[[Category: Lyase]]
 +
[[Category: Multifunctional enzyme]]
 +
[[Category: Pyrimidine biosynthesis]]
 +
[[Category: Transferase]]
 +
[[Category: Ump synthase]]

Current revision

Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP

PDB ID 2qcn

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2qcn"
Personal tools