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.
2qcf
From Proteopedia
| Line 2: | Line 2: | ||
caption="2qcf, resolution 1.22Å" /> | caption="2qcf, resolution 1.22Å" /> | ||
'''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP'''<br /> | '''Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP'''<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== | ||
| - | 2QCF 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=S:'>S</scene>, <scene name='pdbligand=5FU:'>5FU</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=2QCF OCA]. | + | 2QCF 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=S:'>S</scene>, <scene name='pdbligand=5FU:'>5FU</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=AC1:5fu+Binding+Site+For+Residue+A+501'>AC1</scene> and <scene name='pdbsite=AC2:Gol+Binding+Site+For+Residue+A+502'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QCF 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 08:18:19 2008'' |
Revision as of 06:18, 13 February 2008
|
Crystal structure of the orotidine-5'-monophosphate decarboxylase domain (Asp312Asn mutant) of human UMP synthase bound to 5-fluoro-UMP
Contents |
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:[258900]
About this Structure
2QCF 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.
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:18184586
Page seeded by OCA on Wed Feb 13 08:18:19 2008
