4B2X

Pseudomonas aeruginosa RmlA in complex with allosteric inhibitor

4B2X の概要

• エントリーDOI: 10.2210/pdb4b2x/pdb
• 関連するPDBエントリー: 1FXO 1FZW 1G0R 1G1L 1G23 1G2V 1G3L
• 分子名称: GLUCOSE-1-PHOSPHATE THYMIDYLYLTRANSFERASE, 6-amino-1-butyl-5-(cyclopentylamino)pyrimidine-2,4(1H,3H)-dione, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: PSEUDOMONAS AERUGINOSA
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 136058.89

構造登録者

Alphey, M.S.,Pirrie, L.,Torrie, L.S.,Gardiner, M.,Sarkar, A.,Brenk, R.,Westwood, N.J.,Gray, D.,Naismith, J.H. (登録日: 2012-07-18, 公開日: 2012-10-31, 最終更新日: 2023-12-20)

主引用文献

Alphey, M.S.,Pirrie, L.,Torrie, L.S.,Boulkeroua, W.A.,Gardiner, M.,Sarkar, A.,Maringer, M.,Oehlmann, W.,Brenk, R.,Scherman, M.S.,McNeil, M.,Rejzek, M.,Field, R.A.,Singh, M.,Gray, D.,Westwood, N.J.,Naismith, J.H.
Allosteric competitive inhibitors of the glucose-1-phosphate thymidylyltransferase (RmlA) from Pseudomonas aeruginosa.
ACS Chem. Biol., 8:387-396, 2013

PubMed Abstract: Glucose-1-phosphate thymidylyltransferase (RmlA) catalyzes the condensation of glucose-1-phosphate (G1P) with deoxy-thymidine triphosphate (dTTP) to yield dTDP-d-glucose and pyrophosphate. This is the first step in the l-rhamnose biosynthetic pathway. l-Rhamnose is an important component of the cell wall of many microorganisms, including Mycobacterium tuberculosis and Pseudomonas aeruginosa. Here we describe the first nanomolar inhibitors of P. aeruginosa RmlA. These thymine analogues were identified by high-throughput screening and subsequently optimized by a combination of protein crystallography, in silico screening, and synthetic chemistry. Some of the inhibitors show inhibitory activity against M. tuberculosis. The inhibitors do not bind at the active site of RmlA but bind at a second site remote from the active site. Despite this, the compounds act as competitive inhibitors of G1P but with high cooperativity. This novel behavior was probed by structural analysis, which suggests that the inhibitors work by preventing RmlA from undergoing the conformational change key to its ordered bi-bi mechanism.

PubMed: 23138692
DOI: 10.1021/cb300426u

実験手法

X-RAY DIFFRACTION (1.7 Å)