4lp0: Difference between revisions
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==Crystal structure of a topoisomerase ATP inhibitor== | |||
=== | <StructureSection load='4lp0' size='340' side='right' caption='[[4lp0]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4lp0]] 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=4LP0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LP0 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1YM:6-[(ETHYLCARBAMOYL)AMINO]-4-[4-(TRIFLUOROMETHYL)-1,3-THIAZOL-2-YL]-3,3-BIPYRIDINE-5-CARBOXYLIC+ACID'>1YM</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lpb|4lpb]]</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='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=4lp0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lp0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lp0 RCSB], [http://www.ebi.ac.uk/pdbsum/4lp0 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: Basarab, G S | [[Category: Basarab, G S]] | ||
[[Category: Bist, S | [[Category: Bist, S]] | ||
[[Category: Boriack-Sjodin, P A | [[Category: Boriack-Sjodin, P A]] | ||
[[Category: Dangel, B | [[Category: Dangel, B]] | ||
[[Category: Eakin, A E | [[Category: Eakin, A E]] | ||
[[Category: Illingsworth, R | [[Category: Illingsworth, R]] | ||
[[Category: Manchester, J I | [[Category: Manchester, J I]] | ||
[[Category: Sherer, B A | [[Category: Sherer, B A]] | ||
[[Category: Sriram, S | [[Category: Sriram, S]] | ||
[[Category: Uria-Nickelsen, M | [[Category: Uria-Nickelsen, M]] | ||
[[Category: Antimicrobial]] | [[Category: Antimicrobial]] | ||
[[Category: Atp binding]] | [[Category: Atp binding]] | ||
Revision as of 08:59, 5 January 2015
Crystal structure of a topoisomerase ATP inhibitor
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