2qcn

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{{STRUCTURE_2qcn| PDB=2qcn | SCENE= }}
{{STRUCTURE_2qcn| PDB=2qcn | SCENE= }}
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'''Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP'''
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===Covalent complex of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase with 6-iodo-UMP===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_18184586}}
==Disease==
==Disease==
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[[Category: Transferase]]
[[Category: Transferase]]
[[Category: Ump synthase]]
[[Category: Ump synthase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 14:44:17 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 22:03:31 2008''

Revision as of 19:03, 28 July 2008

Image:2qcn.png

Template:STRUCTURE 2qcn

Contents

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

Template:ABSTRACT PUBMED 18184586

Disease

Known disease associated with this structure: Oroticaciduria OMIM:[258900]

About this Structure

2QCN is a Single protein structure of sequence from Homo sapiens. 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 Mon Jul 28 22:03:31 2008

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