3v7c

Cystal structure of SaBPL in complex with inhibitor

spinqualitylabelsall models 3v7c, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3v7c is a 1 chain structure with sequence from Staphylococcus aureus a9781. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: C77 Related: 3v7r, 3v7s, 3v8j, 3v8k, 3v8l Gene: SAOG_00031 (Staphylococcus aureus A9781) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed There is a well-documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes, immune to current resistance mechanisms, which inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3 triazole analogues using click chemistry yielded our most potent structure (Ki 90 nM) with >1100-fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus, but not cultured mammalian cells. The biotin 1,2,3 triazole provides a novel pharmacophore for future medicinal chemistry programmes to develop this new antibiotic class. Selective inhibition of Biotin Protein Ligase from Staphylococcus aureus.,Soares da Costa TP, Tieu W, Yap MY, Pendini NR, Polyak SW, Sejer Pedersen D, Morona R, Turnidge JD, Wallace JC, Wilce MC, Booker GW, Abell AD J Biol Chem. 2012 Mar 21. PMID:22437830 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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