4dq2: Difference between revisions
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== | ==Structure of staphylococcus aureus biotin protein ligase in complex with biotinol-5'-amp== | ||
[[4dq2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <StructureSection load='4dq2' size='340' side='right' caption='[[4dq2]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dq2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staag Staag]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DQ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DQ2 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BTX:((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'>BTX</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ECTR2_1310 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=889933 STAAG])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Biotin--[acetyl-CoA-carboxylase]_ligase Biotin--[acetyl-CoA-carboxylase] ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.15 6.3.4.15] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dq2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dq2 OCA], [http://pdbe.org/4dq2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dq2 RCSB], [http://www.ebi.ac.uk/pdbsum/4dq2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dq2 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 4dq2" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Biotin Protein Ligase|Biotin Protein Ligase]] | *[[Biotin Protein Ligase|Biotin Protein Ligase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
[[Category: | </StructureSection> | ||
[[Category: Booker, G | [[Category: Staag]] | ||
[[Category: Costa, T Soares de | [[Category: Booker, G]] | ||
[[Category: Pendini, N | [[Category: Costa, T Soares de]] | ||
[[Category: Polyak, S | [[Category: Pendini, N]] | ||
[[Category: Tieu, W | [[Category: Polyak, S]] | ||
[[Category: Wallace, J | [[Category: Tieu, W]] | ||
[[Category: Wilce, M | [[Category: Wallace, J]] | ||
[[Category: Yap, M | [[Category: Wilce, M]] | ||
[[Category: Yap, M]] | |||
[[Category: Biotin]] | [[Category: Biotin]] | ||
[[Category: Dna binding domain]] | [[Category: Dna binding domain]] | ||
Revision as of 01:13, 6 August 2016
Structure of staphylococcus aureus biotin protein ligase in complex with biotinol-5'-ampStructure of staphylococcus aureus biotin protein ligase in complex with biotinol-5'-amp
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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