8QIJ

Crystallographic Structure of a Salicylate Synthase from M. abscessus (Mab-SaS)

これはPDB形式変換不可エントリーです。

8QIJ の概要

• エントリーDOI: 10.2210/pdb8qij/pdb
• 分子名称: Putative anthranilate synthase component I TrpE2/ Salicylate synthase MbtI, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: synthase, siderophore, iron acquisition, biosynthetic protein
• 由来する生物種: Mycobacteroides abscessus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99208.40

構造登録者

Cassetta, A.,Covaceuszach, S.,Tomaiuolo, M.,Meneghetti, F.,Villa, S.,Mori, M.,Chiarelli, L.R.,Mangiatordi, G.F. (登録日: 2023-09-12, 公開日: 2024-01-31, 最終更新日: 2024-02-07)

主引用文献

Mori, M.,Cocorullo, M.,Tresoldi, A.,Cazzaniga, G.,Gelain, A.,Stelitano, G.,Chiarelli, L.R.,Tomaiuolo, M.,Delre, P.,Mangiatordi, G.F.,Garofalo, M.,Cassetta, A.,Covaceuszach, S.,Villa, S.,Meneghetti, F.
Structural basis for specific inhibition of salicylate synthase from Mycobacterium abscessus.
Eur.J.Med.Chem., 265:116073-116073, 2024

PubMed Abstract: Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M. abscessus (Mab) has evolved several countermeasures to scavenge iron from host carrier proteins, including the production of siderophores, which play a crucial role in these processes. In this study, we solved, for the first time, the crystal structure of Mab-SaS, the first enzyme involved in the biosynthesis of siderophores. Moreover, we screened a small, focused library and identified a compound exhibiting a potent inhibitory effect against Mab-SaS (IC ≈ 2 μM). Its binding mode was investigated by means of Induced Fit Docking simulations, performed on the crystal structure presented herein. Furthermore, cytotoxicity data and pharmacokinetic predictions revealed the safety and drug-likeness of this class of compounds. Finally, the crystallographic data were used to optimize the model for future virtual screening campaigns. Taken together, the findings of our study pave the way for the identification of potent Mab-SaS inhibitors, based on both established and unexplored chemotypes.

PubMed: 38169270
DOI: 10.1016/j.ejmech.2023.116073

実験手法

X-RAY DIFFRACTION (2.073 Å)