2PQC

CP4 EPSPS liganded with (R)-phosphonate tetrahedral reaction intermediate analog

2PQC の概要

• エントリーDOI: 10.2210/pdb2pqc/pdb
• 関連するPDBエントリー: 2GG4 2GG6 2GGA 2PQ9 2PQB 2PQD
• 分子名称: 3-phosphoshikimate 1-carboxyvinyltransferase, [3R-[3A,4A,5B(R*)]]-5-(1-CARBOXY-1-PHOSPHONOETHOXY)-4-HYDROXY-3-(PHOSPHONOOXY)-1-CYCLOHEXENE-1-CARBOXYLIC ACID (3 entities in total)
• 機能のキーワード: inside-out alpha/beta barrel, transferase
• 由来する生物種: Agrobacterium sp.
• 細胞内の位置: Cytoplasm (Probable): Q9R4E4
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47071.44

構造登録者

Healy-Fried, M.L.,Funke, T.,Han, H.,Schonbrunn, E. (登録日: 2007-05-01, 公開日: 2008-03-11, 最終更新日: 2023-08-30)

主引用文献

Funke, T.,Healy-Fried, M.L.,Han, H.,Alberg, D.G.,Bartlett, P.A.,Schonbrunn, E.
Differential inhibition of class I and class II 5-enolpyruvylshikimate-3-phosphate synthases by tetrahedral reaction intermediate analogues.
Biochemistry, 46:13344-13351, 2007

PubMed Abstract: The shikimate pathway enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSP synthase or EPSPS) is best known as the target of the herbicide glyphosate. EPSPS is also considered an attractive target for the development of novel antibiotics since the pathogenicity of many microorganisms depends on the functionality of the shikimate pathway. Here, we have investigated the inhibitory potency of stable fluorinated or phosphonate-based analogues of the tetrahedral reaction intermediate (TI) in a parallel study utilizing class I (glyphosate-sensitive) and class II (glyphosate-tolerant) EPSPS. The (R)-difluoromethyl and (R)-phosphonate analogues of the TI are the most potent inhibitors of EPSPS described to date. However, we found that class II EPSPS are up to 400 times less sensitive to inhibition by these TI analogues. X-ray crystallographic data revealed that the conformational changes of active site residues observed upon inhibitor binding to the representative class I EPSPS from Escherichia coli do not occur in the prototypical class II enzyme from Agrobacterium sp. strain CP4. It appears that because the active sites of class II EPSPS do not possess the flexibility to accommodate these TI analogues, the analogues themselves undergo conformational changes, resulting in less favorable inhibitory properties. Since pathogenic microorganisms such as Staphylococcus aureus utilize class II EPSPS, we conclude that the rational design of novel EPSPS inhibitors with potential as broad-spectrum antibiotics should be based on the active site structures of class II EPSP synthases.

PubMed: 17958399
DOI: 10.1021/bi701095u

実験手法

X-RAY DIFFRACTION (1.6 Å)