3v7r: Difference between revisions
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==Crystal structure of Staphylococcus aureus biotin protein ligase in complex with inhibitor== | |||
<StructureSection load='3v7r' size='340' side='right'caption='[[3v7r]], [[Resolution|resolution]] 2.61Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3v7r]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_A9781 Staphylococcus aureus A9781]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V7R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3V7R FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.61Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=32G:(3AS,4S,6AR)-4-(5-{1-[4-(6-AMINO-9H-PURIN-9-YL)BUTYL]-1H-1,2,3-TRIAZOL-4-YL}PENTYL)TETRAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-2(3H)-ONE'>32G</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3v7r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v7r OCA], [https://pdbe.org/3v7r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3v7r RCSB], [https://www.ebi.ac.uk/pdbsum/3v7r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3v7r ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:22437830</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3v7r" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Biotin Protein Ligase 3D structures|Biotin Protein Ligase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus A9781]] | |||
[[Category: Pendini NR]] | |||
[[Category: Yap MY]] | |||
Latest revision as of 15:17, 8 November 2023
Crystal structure of Staphylococcus aureus biotin protein ligase in complex with inhibitorCrystal structure of Staphylococcus aureus biotin protein ligase in complex with inhibitor
Structural highlights
Publication Abstract from PubMedThere 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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