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[[Image:2e6y.gif|left|200px]]
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{{STRUCTURE_2e6y|  PDB=2e6y  |  SCENE=  }}
'''Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP'''


==Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP==
<StructureSection load='2e6y' size='340' side='right'caption='[[2e6y]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2e6y]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Methanothermobacter_thermautotrophicus Methanothermobacter thermautotrophicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2E6Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2E6Y 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]] 1.6&#8491;</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=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=2e6y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2e6y OCA], [https://pdbe.org/2e6y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2e6y RCSB], [https://www.ebi.ac.uk/pdbsum/2e6y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2e6y ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PYRF_METTH PYRF_METTH] Catalyzes the decarboxylation of orotidine 5'-monophosphate (OMP) to uridine 5'-monophosphate (UMP).[HAMAP-Rule:MF_01200_A]
== 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/e6/2e6y_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=2e6y ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5'-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5'-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 A resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-72 [corrected] residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC50s of 4.4 +/- 1.3 microM and 6.2 +/- 0.7 microM against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.


==Overview==
A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity.,Bello AM, Poduch E, Fujihashi M, Amani M, Li Y, Crandall I, Hui R, Lee PI, Kain KC, Pai EF, Kotra LP J Med Chem. 2007 Mar 8;50(5):915-21. Epub 2007 Feb 10. PMID:17290979<ref>PMID:17290979</ref>
Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze the decarboxylation of orotidine 5'-monophosphate without any covalent intermediates. Active site residues in ODCase are involved in an extensive hydrogen-bonding network. We discovered that 6-iodouridine 5'-monophosphate (6-iodo-UMP) irreversibly inhibits the catalytic activities of ODCases from Methanobacterium thermoautotrophicum and Plasmodium falciparum. Mass spectral analysis of the enzyme-inhibitor complex confirms covalent attachment of the inhibitor to ODCase accompanied by the loss of two protons and the iodo moiety. The X-ray crystal structure (1.6 A resolution) of the complex of the inhibitor and ODCase clearly shows the covalent bond formation with the active site Lys-72 [corrected] residue. 6-Iodo-UMP inhibits ODCase in a time- and concentration-dependent fashion. 6-Iodouridine, the nucleoside form of 6-iodo-UMP, exhibited potent antiplasmodial activity, with IC50s of 4.4 +/- 1.3 microM and 6.2 +/- 0.7 microM against P. falciparum ItG and 3D7 isolates, respectively. 6-Iodouridine 5'-monophosphate is a novel covalent inhibitor of ODCase, and its nucleoside analogue paves the way to a new class of inhibitors against malaria.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2E6Y is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Methanothermobacter_thermautotrophicus Methanothermobacter thermautotrophicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2E6Y OCA].
</div>
<div class="pdbe-citations 2e6y" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
A potent, covalent inhibitor of orotidine 5'-monophosphate decarboxylase with antimalarial activity., Bello AM, Poduch E, Fujihashi M, Amani M, Li Y, Crandall I, Hui R, Lee PI, Kain KC, Pai EF, Kotra LP, J Med Chem. 2007 Mar 8;50(5):915-21. Epub 2007 Feb 10. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17290979 17290979]
*[[Uridine 5'-monophosphate synthase 3D structures|Uridine 5'-monophosphate synthase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Methanothermobacter thermautotrophicus]]
[[Category: Methanothermobacter thermautotrophicus]]
[[Category: Orotidine-5'-phosphate decarboxylase]]
[[Category: Bello AM]]
[[Category: Single protein]]
[[Category: Fujihashi M]]
[[Category: Bello, A M.]]
[[Category: Kotra LP]]
[[Category: Fujihashi, M.]]
[[Category: Pai EF]]
[[Category: Kotra, L P.]]
[[Category: Pai, E F.]]
[[Category: Tim-barrel]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 02:02:42 2008''

Latest revision as of 07:52, 23 October 2024

Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP

2e6y, resolution 1.60Å

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