6Z0Q

Crystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with fragment 2

6Z0Q の概要

• エントリーDOI: 10.2210/pdb6z0q/pdb
• 分子名称: Phosphoribosylaminoimidazole-succinocarboxamide synthase, ethyl (2~{S},3~{R})-3-(5-bromanylpyridin-2-yl)-2-fluoranyl-3-oxidanyl-propanoate, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: saicar synthetase, phosphoribosylaminoimidazole-succinocarboxamide synthase, purc, purine biosynthesis, ligase
• 由来する生物種: Mycobacteroides abscessus ATCC 19977
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34288.34

構造登録者

Thomas, S.E.,Charoensutthivarakul, S.,Coyne, A.G.,Abell, C.,Blundell, T.L. (登録日: 2020-05-10, 公開日: 2021-05-19, 最終更新日: 2024-01-24)

主引用文献

Charoensutthivarakul, S.,Thomas, S.E.,Curran, A.,Brown, K.P.,Belardinelli, J.M.,Whitehouse, A.J.,Acebron-Garcia-de-Eulate, M.,Sangan, J.,Gramani, S.G.,Jackson, M.,Mendes, V.,Floto, R.A.,Blundell, T.L.,Coyne, A.G.,Abell, C.
Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.
Acs Infect Dis., 8:296-309, 2022

PubMed Abstract: has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against and This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from .

PubMed: 35037462
DOI: 10.1021/acsinfecdis.1c00432

実験手法

X-RAY DIFFRACTION (1.535 Å)