5SNU

PanDDA analysis group deposition -- Crystal Structure of Pseudomonas Aeruginosa FabF-C164Q mutant protein in complex with Z2856434770

5SNU の概要

• エントリーDOI: 10.2210/pdb5snu/pdb
• Group deposition: PanDDA analysis group deposition (G_1002234)
• 分子名称: 3-oxoacyl-[acyl-carrier-protein] synthase 2, DIMETHYL SULFOXIDE, 1-(3-chlorophenyl)-N-methylmethanamine, ... (5 entities in total)
• 機能のキーワード: sgc - diamond i04-1 fragment screening, pandda, xchemexplorer, fabf, beta-ketoacyl-acyl-carrier-protein synthase ii, transferase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88169.93

構造登録者

Brenk, R.,Georgiou, C. (登録日: 2022-05-30, 公開日: 2023-12-20, 最終更新日: 2025-05-07)

主引用文献

Georgiou, C.,Espeland, L.O.,Bukya, H.,Yadrykhins'ky, V.,Haug, B.E.,Mainkar, P.S.,Brenk, R.
Towards new antibiotics: P. aeruginosa FabF ligands discovered by crystallographic fragment screening followed by hit expansion.
Eur.J.Med.Chem., 291:117563-117563, 2025

PubMed Abstract: There is an urgent need for new antibiotics. 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. Very few inhibitors of FabF are known and most are derived from natural products. In an effort to further explore the chemical space of FabF ligands, we have carried out fragment screening by X-ray crystallography against an intermediated state-mimicking variant of P. aeruginosa FabF (PaFabF C164Q). This screen has resulted in 48 hits out of which 16 bind in or close to the malonyl-CoA or fatty acid binding site or an adjacent dimer interface. None of the closer investigated fragments were active in a binding assay, but the same was the case for fragments derived from a potent FabF inhibitor. For hit optimization, we focused on the two fragments binding close to the catalytic residues of FabF. Different strategies were followed in the optimization process: exploration of commercially available analogues, fragment merging, virtual screening of a combinatorial make-on-demand space, and design and in-house synthesis of analogues. In total, more than 90 analogues of the hit compounds were explored, and for 10 of those co-crystal structures could be determined. The most potent ligand was discovered using manual structure-based design and has a binding affinity of 65 μM. This data package forms a strong foundation for the development of more potent and diverse FabF inhibitors.

PubMed: 40233425
DOI: 10.1016/j.ejmech.2025.117563

実験手法

X-RAY DIFFRACTION (1.98 Å)