4lpb: Difference between revisions
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==Crystal structure of a topoisomerase ATPase inhibitor== | |||
=== | <StructureSection load='4lpb' size='340' side='right' caption='[[4lpb]], [[Resolution|resolution]] 1.75Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4lpb]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Strr6 Strr6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LPB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LPB FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1YP:1-ETHYL-3-{5-(5-OXO-4,5-DIHYDRO-1,3,4-OXADIAZOL-2-YL)-4-[4-(TRIFLUOROMETHYL)-1,3-THIAZOL-2-YL]-3,3-BIPYRIDIN-6-YL}UREA'>1YP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lp0|4lp0]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">parE, spr0756 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=171101 STRR6])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_topoisomerase_(ATP-hydrolyzing) DNA topoisomerase (ATP-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.3 5.99.1.3] </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=4lpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lpb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lpb RCSB], [http://www.ebi.ac.uk/pdbsum/4lpb PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The discovery and optimization of a new class of bacterial topoisomerase (DNA gyrase and topoisomerase IV) inhibitors binding in the ATP domain are described. A fragment molecule, 1-ethyl-3-(2-pyridyl)urea, provided sufficiently potent enzyme inhibition (32 muM) to prompt further analogue work. Acids and acid isosteres were incorporated at the 5-pyridyl position of this fragment, bridging to a key asparagine residue, improving enzyme inhibition, and leading to measurable antibacterial activity. A CF3-thiazole substituent at the 4-pyridyl position improved inhibitory potency due to a favorable lipophilic interaction. Promising antibacterial activity was seen versus the Gram-positive pathogens Staphylococcus aureus and Streptococcus pneumoniae and the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis . Precursor metabolite incorporation and mutant analysis studies support the mode-of-action, blockage of DNA synthesis by dual target topoisomerase inhibition. Compound 35 was efficacious in a mouse S. aureus disease model, where a 4.5-log reduction in colony forming units versus control was demonstrated. | |||
Fragment-to-Hit-to-Lead Discovery of a Novel Pyridylurea Scaffold of ATP Competitive Dual Targeting Type II Topoisomerase Inhibiting Antibacterial Agents.,Basarab GS, Manchester JI, Bist S, Boriack-Sjodin PA, Dangel B, Illingworth R, Sherer BA, Sriram S, Uria-Nickelsen M, Eakin AE J Med Chem. 2013 Oct 29. PMID:24098982<ref>PMID:24098982</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
==See Also== | |||
*[[Topoisomerase|Topoisomerase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Strr6]] | [[Category: Strr6]] | ||
[[Category: Boriack-Sjodin, A | [[Category: Boriack-Sjodin, A]] | ||
[[Category: Antimicrobial]] | [[Category: Antimicrobial]] | ||
[[Category: Atp binding]] | [[Category: Atp binding]] | ||
Revision as of 09:38, 5 January 2015
Crystal structure of a topoisomerase ATPase inhibitor
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