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[[ | ==Crystal structure of dehydrosqualene synthase (crtm) from s. aureus complexed with bph-1034, mg2+ and fmp.== | ||
<StructureSection load='4f6v' size='340' side='right' caption='[[4f6v]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4f6v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F6V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F6V FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FJP:(2E,6Z)-3,7,11-TRIMETHYLDODECA-2,6,10-TRIEN-1-YL+DIHYDROGEN+PHOSPHATE'>FJP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SRT:S,R+MESO-TARTARIC+ACID'>SRT</scene>, <scene name='pdbligand=ZYM:2,4-DIOXO-4-{[3-(3-PHENOXYPHENYL)PROPYL]AMINO}BUTANOIC+ACID'>ZYM</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">crtM ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 Staphylococcus aureus])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/4,4'-diapophytoene_synthase 4,4'-diapophytoene synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.96 2.5.1.96] </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=4f6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4f6v RCSB], [http://www.ebi.ac.uk/pdbsum/4f6v PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg(2+)/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the x-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg(2+) binding hypothesis, together with the x-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound 45 had cell growth inhibition MIC(90) values of ~250-500 ng/mL against S. aureus, 500 ng/mL against Bacillus anthracis, 4 mug/mL against Listeria monocytogenes and Enterococcus faecium, and 1 mug/mL against Streptococcus pyogenes M1, but very little activity against E. coli (DH5alpha, K12) or human cell lines. | |||
HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis.,Zhang Y, Fu-Yang Lin, Li K, Zhu W, Liu YL, Cao R, Pang R, Lee E, Axelson J, Hensler M, Wang K, Molohon KJ, Wang Y, Mitchell DA, Nizet V, Oldfield E ACS Med Chem Lett. 2012 Apr 3;3(5):402-406. PMID:22662288<ref>PMID:22662288</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
< | |||
[[Category: 4,4'-diapophytoene synthase]] | [[Category: 4,4'-diapophytoene synthase]] | ||
[[Category: Staphylococcus aureus]] | [[Category: Staphylococcus aureus]] | ||
[[Category: Lin, F Y | [[Category: Lin, F Y]] | ||
[[Category: Liu, Y L | [[Category: Liu, Y L]] | ||
[[Category: Oldfield, E | [[Category: Oldfield, E]] | ||
[[Category: Zhang, Y | [[Category: Zhang, Y]] | ||
[[Category: Bph-1034]] | [[Category: Bph-1034]] | ||
[[Category: Dehydrosqualene synthase]] | [[Category: Dehydrosqualene synthase]] | ||
Revision as of 08:48, 25 December 2014
Crystal structure of dehydrosqualene synthase (crtm) from s. aureus complexed with bph-1034, mg2+ and fmp.Crystal structure of dehydrosqualene synthase (crtm) from s. aureus complexed with bph-1034, mg2+ and fmp.
Structural highlights
Publication Abstract from PubMedWe report the discovery of antibacterial leads, keto- and diketo-acids, targeting two prenyl transferases: undecaprenyl diphosphate synthase (UPPS) and dehydrosqualene synthase (CrtM). The leads were suggested by the observation that keto- and diketo-acids bind to the active site Mg(2+)/Asp domain in HIV-1 integrase, and similar domains are present in prenyl transferases. We report the x-ray crystallographic structures of one diketo-acid and one keto-acid bound to CrtM, which supports the Mg(2+) binding hypothesis, together with the x-ray structure of one diketo-acid bound to UPPS. In all cases, the inhibitors bind to a farnesyl diphosphate substrate-binding site. Compound 45 had cell growth inhibition MIC(90) values of ~250-500 ng/mL against S. aureus, 500 ng/mL against Bacillus anthracis, 4 mug/mL against Listeria monocytogenes and Enterococcus faecium, and 1 mug/mL against Streptococcus pyogenes M1, but very little activity against E. coli (DH5alpha, K12) or human cell lines. HIV-1 Integrase Inhibitor-Inspired Antibacterials Targeting Isoprenoid Biosynthesis.,Zhang Y, Fu-Yang Lin, Li K, Zhu W, Liu YL, Cao R, Pang R, Lee E, Axelson J, Hensler M, Wang K, Molohon KJ, Wang Y, Mitchell DA, Nizet V, Oldfield E ACS Med Chem Lett. 2012 Apr 3;3(5):402-406. PMID:22662288[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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