6YYD
Crystal structure of SAICAR Synthetase (PurC) from Mycobacterium abscessus in complex with inhibitor
Summary for 6YYD
| Entry DOI | 10.2210/pdb6yyd/pdb |
| Descriptor | Phosphoribosylaminoimidazole-succinocarboxamide synthase, 4-azanyl-6-[1-[[3,4-bis(fluoranyl)phenyl]methyl]pyrazol-4-yl]pyrimidine-5-carbonitrile, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | saicar synthetase, phosphoribosylaminoimidazole-succinocarboxamide synthase, purc, purine biosynthesis, ligase |
| Biological source | Mycobacteroides abscessus (strain ATCC 19977 / DSM 44196 / CIP 104536 / JCM 13569 / NCTC 13031 / TMC 1543) |
| Total number of polymer chains | 1 |
| Total formula weight | 34370.58 |
| Authors | Thomas, S.E.,Charoensutthivarakul, S.,Coyne, A.G.,Abell, C.,Blundell, T.L. (deposition date: 2020-05-04, release date: 2021-05-12, 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 Cited by 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: 35037462DOI: 10.1021/acsinfecdis.1c00432 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.387 Å) |
Structure validation
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