6CCN

Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with (R)-2,4-dihydroxy-N-(2-(4-hydroxy-1H-benzo[d]imidazol-2-yl)ethyl)-3,3-dimethylbutanamide

6CCN の概要

• エントリーDOI: 10.2210/pdb6ccn/pdb
• 分子名称: Phosphopantetheine adenylyltransferase, (2R)-2,4-dihydroxy-N-[2-(7-hydroxy-1H-benzimidazol-2-yl)ethyl]-3,3-dimethylbutanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: ppat coad fbdd phosphopantetheine adenylyltransferase gram-negative antibacterial antibiotic, transferase, transferase-antibiotic complex, transferase/antibiotic
• 由来する生物種: Escherichia coli (strain K12)
• 細胞内の位置: Cytoplasm : P0A6I6
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37338.76

構造登録者

Mamo, M.,Appleton, B.A. (登録日: 2018-02-07, 公開日: 2018-03-14, 最終更新日: 2024-03-13)

主引用文献

Moreau, R.J.,Skepper, C.K.,Appleton, B.A.,Blechschmidt, A.,Balibar, C.J.,Benton, B.M.,Drumm, J.E.,Feng, B.Y.,Geng, M.,Li, C.,Lindvall, M.K.,Lingel, A.,Lu, Y.,Mamo, M.,Mergo, W.,Polyakov, V.,Smith, T.M.,Takeoka, K.,Uehara, K.,Wang, L.,Wei, J.R.,Weiss, A.H.,Xie, L.,Xu, W.,Zhang, Q.,de Vicente, J.
Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.
J. Med. Chem., 61:3309-3324, 2018

PubMed Abstract: The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli Δ tolC mutant strain.

PubMed: 29498517
DOI: 10.1021/acs.jmedchem.7b01691

実験手法

X-RAY DIFFRACTION (1.87 Å)