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| | ==Pyrrolopyrimidine inhibitors of dna gyrase b and topoisomerase iv, part i: structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity== | | ==Pyrrolopyrimidine inhibitors of dna gyrase b and topoisomerase iv, part i: structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity== |
| - | <StructureSection load='4hz5' size='340' side='right' caption='[[4hz5]], [[Resolution|resolution]] 2.70Å' scene=''> | + | <StructureSection load='4hz5' size='340' side='right'caption='[[4hz5]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hz5]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Entfa Entfa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HZ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HZ5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hz5]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterococcus_faecalis_V583 Enterococcus faecalis V583]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HZ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HZ5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19Y:6-ETHYL-4-METHOXY-2-(PYRIDIN-3-YLSULFANYL)-7H-PYRROLO[2,3-D]PYRIMIDINE-5-CARBALDEHYDE'>19Y</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19Y:6-ETHYL-4-METHOXY-2-(PYRIDIN-3-YLSULFANYL)-7H-PYRROLO[2,3-D]PYRIMIDINE-5-CARBALDEHYDE'>19Y</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hz0|4hz0]], [[4hyp|4hyp]], [[4hym|4hym]], [[4hy1|4hy1]], [[4hxz|4hxz]], [[4ggl|4ggl]], [[4gfn|4gfn]], [[4gee|4gee]], [[4hxw|4hxw]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4hz5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hz5 OCA], [https://pdbe.org/4hz5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hz5 RCSB], [https://www.ebi.ac.uk/pdbsum/4hz5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hz5 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">parE, EF_1615 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=226185 ENTFA])</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=4hz5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hz5 OCA], [http://pdbe.org/4hz5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hz5 RCSB], [http://www.ebi.ac.uk/pdbsum/4hz5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hz5 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/H7C794_ENTFA H7C794_ENTFA]] Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.[HAMAP-Rule:MF_00939] | + | [https://www.uniprot.org/uniprot/PARE_ENTFA PARE_ENTFA] Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA (PubMed:23352267). Performs the decatenation events required during the replication of a circular DNA molecule.[HAMAP-Rule:MF_00938]<ref>PMID:23352267</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Topoisomerase|Topoisomerase]] | + | *[[Topoisomerase 3D structures|Topoisomerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Entfa]] | + | [[Category: Enterococcus faecalis V583]] |
| - | [[Category: Bensen, D C]] | + | [[Category: Large Structures]] |
| - | [[Category: Creighton, C J]] | + | [[Category: Bensen DC]] |
| - | [[Category: Tari, L W]] | + | [[Category: Creighton CJ]] |
| - | [[Category: Atp-binding]] | + | [[Category: Tari LW]] |
| - | [[Category: Atp-binding domain]]
| + | |
| - | [[Category: Isomerase-isomerase inhibitor complex]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Topoisomerase]]
| + | |
| Structural highlights
Function
PARE_ENTFA Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA (PubMed:23352267). Performs the decatenation events required during the replication of a circular DNA molecule.[HAMAP-Rule:MF_00938][1]
Publication Abstract from PubMed
The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.
Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity.,Tari LW, Trzoss M, Bensen DC, Li X, Chen Z, Lam T, Zhang J, Creighton CJ, Cunningham ML, Kwan B, Stidham M, Shaw KJ, Lightstone FC, Wong SE, Nguyen TB, Nix J, Finn J Bioorg Med Chem Lett. 2012 Dec 5. pii: S0960-894X(12)01475-8. doi:, 10.1016/j.bmcl.2012.11.032. PMID:23352267[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tari LW, Trzoss M, Bensen DC, Li X, Chen Z, Lam T, Zhang J, Creighton CJ, Cunningham ML, Kwan B, Stidham M, Shaw KJ, Lightstone FC, Wong SE, Nguyen TB, Nix J, Finn J. Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity. Bioorg Med Chem Lett. 2012 Dec 5. pii: S0960-894X(12)01475-8. doi:, 10.1016/j.bmcl.2012.11.032. PMID:23352267 doi:http://dx.doi.org/10.1016/j.bmcl.2012.11.032
- ↑ Tari LW, Trzoss M, Bensen DC, Li X, Chen Z, Lam T, Zhang J, Creighton CJ, Cunningham ML, Kwan B, Stidham M, Shaw KJ, Lightstone FC, Wong SE, Nguyen TB, Nix J, Finn J. Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity. Bioorg Med Chem Lett. 2012 Dec 5. pii: S0960-894X(12)01475-8. doi:, 10.1016/j.bmcl.2012.11.032. PMID:23352267 doi:http://dx.doi.org/10.1016/j.bmcl.2012.11.032
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