2qcc: Difference between revisions
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caption="2qcc, resolution 1.85Å" /> | caption="2qcc, resolution 1.85Å" /> | ||
'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase, apo form'''<br /> | '''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase, apo form'''<br /> | ||
==Overview== | |||
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. | |||
==Disease== | |||
Known disease associated with this structure: Oroticaciduria OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=258900 258900]] | |||
==About this Structure== | ==About this Structure== | ||
2QCC 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> 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=2QCC OCA]. | 2QCC 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> 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] Known structural/functional Sites: <scene name='pdbsite=AC1:So4+Binding+Site+For+Residue+A+481'>AC1</scene>, <scene name='pdbsite=AC2:So4+Binding+Site+For+Residue+B+481'>AC2</scene>, <scene name='pdbsite=AC3:Gol+Binding+Site+For+Residue+A+482'>AC3</scene> and <scene name='pdbsite=AC4:Gol+Binding+Site+For+Residue+B+482'>AC4</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCC OCA]. | ||
==Reference== | |||
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] | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Orotidine-5'-phosphate decarboxylase]] | [[Category: Orotidine-5'-phosphate decarboxylase]] | ||
| Line 18: | Line 27: | ||
[[Category: ump synthase]] | [[Category: ump synthase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 13 08:18:16 2008'' | ||
Revision as of 09:18, 13 February 2008
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Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase, apo form
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Oroticaciduria OMIM:[258900]
About this StructureAbout this Structure
2QCC is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Orotidine-5'-phosphate decarboxylase, with EC number 4.1.1.23 Known structural/functional Sites: , , and . Full crystallographic information is available from OCA.
ReferenceReference
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
Page seeded by OCA on Wed Feb 13 08:18:16 2008