2QCC

Crystal structure of the orotidine-5'-monophosphate decarboxylase domain of human UMP synthase, apo form

2QCC の概要

• エントリーDOI: 10.2210/pdb2qcc/pdb
• 関連するPDBエントリー: 2jgy 2v30
• 分子名称: Orotidine 5'- phosphate decarboxylase (OMPdecase), SULFATE ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: ump synthase, decarboxylase, tim barrel, catalytic proficiency, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56975.80

構造登録者

Wittmann, J.,Rudolph, M. (登録日: 2007-06-19, 公開日: 2007-11-06, 最終更新日: 2024-02-21)

主引用文献

Wittmann, J.G.,Heinrich, D.,Gasow, K.,Frey, A.,Diederichsen, U.,Rudolph, M.G.
Structures of the human orotidine-5'-monophosphate decarboxylase support a covalent mechanism and provide a framework for drug design.
Structure, 16:82-92, 2008

PubMed Abstract: 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.

PubMed: 18184586
DOI: 10.1016/j.str.2007.10.020

実験手法

X-RAY DIFFRACTION (1.85 Å)