6Z0Q

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

Summary for 6Z0Q

• Entry DOI: 10.2210/pdb6z0q/pdb
• Descriptor: Phosphoribosylaminoimidazole-succinocarboxamide synthase, ethyl (2~{S},3~{R})-3-(5-bromanylpyridin-2-yl)-2-fluoranyl-3-oxidanyl-propanoate, SULFATE ION, ... (4 entities in total)
• Functional Keywords: saicar synthetase, phosphoribosylaminoimidazole-succinocarboxamide synthase, purc, purine biosynthesis, ligase
• Biological source: Mycobacteroides abscessus ATCC 19977
• Total number of polymer chains: 1
• Total formula weight: 34288.34

Authors

Thomas, S.E.,Charoensutthivarakul, S.,Coyne, A.G.,Abell, C.,Blundell, T.L. (deposition date: 2020-05-10, release date: 2021-05-19, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.535 Å)