4DQ2

Structure of staphylococcus aureus biotin protein ligase in complex with biotinol-5'-amp

Summary for 4DQ2

• Entry DOI: 10.2210/pdb4dq2/pdb
• Descriptor: Biotin-[acetyl-CoA-carboxylase] ligase, ((2R,3S,4R,5R)-5-(6-AMINO-9H-PURIN-9-YL)-3,4-DIHYDROXY-TETRAHYDROFURAN-2-YL)METHYL 5-((3AS,4S,6AR)-2-OXO-HEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL)PENTYL HYDROGEN PHOSPHATE (3 entities in total)
• Functional Keywords: dna binding domain, metabolism, biotin, ligate, ligase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 38443.17

Authors

Wilce, M.,Yap, M.,Pendini, N.,Soares de Costa, T.,Polyak, S.,Tieu, W.,Booker, G.,Wallace, J. (deposition date: 2012-02-14, release date: 2012-04-18, Last modification date: 2024-03-20)

Primary citation

Soares da Costa, T.P.,Tieu, W.,Yap, M.Y.,Pendini, N.R.,Polyak, S.W.,Sejer Pedersen, D.,Morona, R.,Turnidge, J.D.,Wallace, J.C.,Wilce, M.C.,Booker, G.W.,Abell, A.D.
Selective inhibition of biotin protein ligase from Staphylococcus aureus.
J.Biol.Chem., 287:17823-17832, 2012

PubMed Abstract: 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 that 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 (K(i) 90 nM) with a >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 programs to develop this new antibiotic class.

PubMed: 22437830
DOI: 10.1074/jbc.M112.356576

Experimental method

X-RAY DIFFRACTION (2.5 Å)