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2e6y
From Proteopedia
(New page: 200px<br /><applet load="2e6y" size="450" color="white" frame="true" align="right" spinBox="true" caption="2e6y, resolution 1.60Å" /> '''Covalent complex of ...) |
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| - | [[Image:2e6y.gif|left|200px]]<br /><applet load="2e6y" size=" | + | [[Image:2e6y.gif|left|200px]]<br /><applet load="2e6y" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2e6y, resolution 1.60Å" /> | caption="2e6y, resolution 1.60Å" /> | ||
'''Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP'''<br /> | '''Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Orotidine 5'-monophosphate decarboxylase (ODCase) has evolved to catalyze | + | 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== | ==About this Structure== | ||
| - | 2E6Y is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Methanothermobacter_thermautotrophicus Methanothermobacter thermautotrophicus] with U5P and GOL 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:// | + | 2E6Y is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Methanothermobacter_thermautotrophicus Methanothermobacter thermautotrophicus] with <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=2E6Y OCA]. |
==Reference== | ==Reference== | ||
| - | A | + | 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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17290979 17290979] |
[[Category: Methanothermobacter thermautotrophicus]] | [[Category: Methanothermobacter thermautotrophicus]] | ||
[[Category: Orotidine-5'-phosphate decarboxylase]] | [[Category: Orotidine-5'-phosphate decarboxylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bello, A | + | [[Category: Bello, A M.]] |
[[Category: Fujihashi, M.]] | [[Category: Fujihashi, M.]] | ||
| - | [[Category: Kotra, L | + | [[Category: Kotra, L P.]] |
| - | [[Category: Pai, E | + | [[Category: Pai, E F.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: U5P]] | [[Category: U5P]] | ||
[[Category: tim-barrel]] | [[Category: tim-barrel]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:06:43 2008'' |
Revision as of 15:06, 21 February 2008
|
Covalent complex of orotidine 5'-monophosphate decarboxylase (ODCase) with 6-Iodo-UMP
Overview
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
2E6Y is a Single protein structure of sequence from Methanothermobacter thermautotrophicus with and as ligands. Active as Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 17:06:43 2008
