PDBsum entry 6ccs

Transferase/antibiotic

PDB id: 6ccs

Contents

Protein chains

158 a.a.

Ligands

EXD ×2

SO4 ×5

Waters ×188

PDB id:

6ccs

Name:

Transferase/antibiotic

Title:

Crystal structure of e.Coli phosphopantetheine adenylyltransferase (ppat/coad) in complex with 2-(trifluoromethyl)-1h-benzo[d]imidazol- 4-ol

Structure:

Phosphopantetheine adenylyltransferase. Chain: a, b. Synonym: dephospho-coa pyrophosphorylase,pantetheine-phosphate adenylyltransferase,ppat. Engineered: yes

Source:

Escherichia coli (strain k12). Organism_taxid: 83333. Strain: k12. Gene: coad, kdtb, yica, b3634, jw3609. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.06Å R-factor: 0.192 R-free: 0.219

Authors:

M.Mamo,B.A.Appleton

Key ref:

R.J.Moreau et al. (2018). Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria. J Med Chem, 61, 3309-3324. PubMed id: 29498517 DOI: 10.1021/acs.jmedchem.7b01691

Date:

07-Feb-18 Release date: 14-Mar-18

Protein chains

P0A6I6  (COAD_ECOLI) -  Phosphopantetheine adenylyltransferase from Escherichia coli (strain K12)

Seq: 159 a.a.

Struc: 158 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.7.3 - pantetheine-phosphate adenylyltransferase.
• Pathway: Coenzyme A Biosynthesis (late stages)
• Reaction: (R)-4'-phosphopantetheine + ATP + H⁺ = 3'-dephospho-CoA + diphosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acs.jmedchem.7b01691

J Med Chem 61:3309-3324 (2018)

PubMed id: 29498517

Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.

R.J.Moreau, C.K.Skepper, B.A.Appleton, A.Blechschmidt, C.J.Balibar, B.M.Benton, J.E.Drumm, B.Y.Feng, M.Geng, C.Li, M.K.Lindvall, A.Lingel, Y.Lu, M.Mamo, W.Mergo, V.Polyakov, T.M.Smith, K.Takeoka, K.Uehara, L.Wang, J.R.Wei, A.H.Weiss, L.Xie, W.Xu, Q.Zhang, J.de Vicente.

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.