7OC0

Structure of Pseudomonas aeruginosa FabF mutant C164Q in complex with a ligand (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid

Summary for 7OC0

• Entry DOI: 10.2210/pdb7oc0/pdb
• Descriptor: 3-oxoacyl-[acyl-carrier-protein] synthase 2, (2S,4R)-2-(thiophen-2-yl)thiazolidine-4-carboxylic acid, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: inhibitor, antibiotic, fatty acid biosynthesis pathway
• Biological source: Pseudomonas aeruginosa PAO1
• Total number of polymer chains: 2
• Total formula weight: 87569.12

Authors

Georgiou, C.,Brenk, R.,Espeland, L.O.,Klein, R. (deposition date: 2021-04-25, release date: 2021-08-25, Last modification date: 2024-10-23)

Primary citation

Espeland, L.O.,Georgiou, C.,Klein, R.,Bhukya, H.,Haug, B.E.,Underhaug, J.,Mainkar, P.S.,Brenk, R.
An Experimental Toolbox for Structure-Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics.
Chemmedchem, 16:2715-2726, 2021

PubMed Abstract: FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF.

PubMed: 34189850
DOI: 10.1002/cmdc.202100302

Experimental method

X-RAY DIFFRACTION (1.78 Å)