5so1

PanDDA analysis group deposition -- Crystal Structure of Pseudomonas Aeruginosa FabF-C164Q mutant protein in complex with Z30620520

spinqualitylabelsall models 5so1, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5so1 is a 2 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.07Å Ligands: DMS, GX4, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function G3XDA2_PSEAE Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP (By similarity).[PIRNR:PIRNR000447] Publication Abstract from PubMed 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 muM. This data package forms a strong foundation for the development of more potent and diverse FabF inhibitors. Towards new antibiotics: P. aeruginosa FabF ligands discovered by crystallographic fragment screening followed by hit expansion.,Georgiou C, Espeland LO, Bukya H, Yadrykhins'ky V, Haug BE, Mainkar PS, Brenk R Eur J Med Chem. 2025 Apr 3;291:117563. doi: 10.1016/j.ejmech.2025.117563. PMID:40233425 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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