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4lpb

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==Crystal structure of a topoisomerase ATPase inhibitor==
==Crystal structure of a topoisomerase ATPase inhibitor==
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<StructureSection load='4lpb' size='340' side='right' caption='[[4lpb]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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<StructureSection load='4lpb' size='340' side='right'caption='[[4lpb]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<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>
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<table><tr><td colspan='2'>[[4lpb]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptococcus_pneumoniae_R6 Streptococcus pneumoniae R6]. 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 [https://proteopedia.org/fgij/fg.htm?mol=4LPB FirstGlance]. <br>
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</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lp0|4lp0]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lpb OCA], [https://pdbe.org/4lpb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lpb RCSB], [https://www.ebi.ac.uk/pdbsum/4lpb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lpb ProSAT]</span></td></tr>
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<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>
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<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://pdbe.org/4lpb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lpb RCSB], [http://www.ebi.ac.uk/pdbsum/4lpb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lpb ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q8DQB5_STRR6 Q8DQB5_STRR6]
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4lpb" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Topoisomerase|Topoisomerase]]
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*[[Topoisomerase 3D structures|Topoisomerase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Strr6]]
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[[Category: Large Structures]]
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[[Category: Boriack-Sjodin, A]]
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[[Category: Streptococcus pneumoniae R6]]
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[[Category: Antimicrobial]]
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[[Category: Boriack-Sjodin A]]
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[[Category: Atp binding]]
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[[Category: Atp binding domain]]
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[[Category: Isomerase-isomerase inhibitor complex]]
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[[Category: Protein-inhibitor complex]]
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[[Category: Structure-based drug design]]
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[[Category: Virtual screen]]
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Current revision

Crystal structure of a topoisomerase ATPase inhibitor

PDB ID 4lpb

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