4hyp: Difference between revisions

Revision as of 08:27, 9 November 2022

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.

Structural highlights

4hyp is a 4 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	1A1, MG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GYRB_ECOLI DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.^[1] ^[2] ^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Noble CG, Maxwell A. The role of GyrB in the DNA cleavage-religation reaction of DNA gyrase: a proposed two metal-ion mechanism. J Mol Biol. 2002 Apr 26;318(2):361-71. PMID:12051843 doi:https://dx.doi.org/10.1016/S0022-2836(02)00049-9
↑ Sissi C, Chemello A, Vazquez E, Mitchenall LA, Maxwell A, Palumbo M. DNA gyrase requires DNA for effective two-site coordination of divalent metal ions: further insight into the mechanism of enzyme action. Biochemistry. 2008 Aug 19;47(33):8538-45. doi: 10.1021/bi800480j. Epub 2008 Jul, 22. PMID:18642932 doi:https://dx.doi.org/10.1021/bi800480j
↑ Schoeffler AJ, May AP, Berger JM. A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function. Nucleic Acids Res. 2010 Jul 31. PMID:20675723 doi:10.1093/nar/gkq665
↑ 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:https://dx.doi.org/10.1016/j.bmcl.2012.11.032

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Noble CG, Maxwell A. The role of GyrB in the DNA cleavage-religation reaction of DNA gyrase: a proposed two metal-ion mechanism. J Mol Biol. 2002 Apr 26;318(2):361-71. PMID:12051843 doi:https://dx.doi.org/10.1016/S0022-2836(02)00049-9

[2] Sissi C, Chemello A, Vazquez E, Mitchenall LA, Maxwell A, Palumbo M. DNA gyrase requires DNA for effective two-site coordination of divalent metal ions: further insight into the mechanism of enzyme action. Biochemistry. 2008 Aug 19;47(33):8538-45. doi: 10.1021/bi800480j. Epub 2008 Jul, 22. PMID:18642932 doi:https://dx.doi.org/10.1021/bi800480j

[3] Schoeffler AJ, May AP, Berger JM. A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function. Nucleic Acids Res. 2010 Jul 31. PMID:20675723 doi:10.1093/nar/gkq665

[4] 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:https://dx.doi.org/10.1016/j.bmcl.2012.11.032

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
 ==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='4hyp' size='340' side='right' caption='[[4hyp]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+<StructureSection load='4hyp' size='340' side='right'caption='[[4hyp]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4hyp]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HYP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HYP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4hyp]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HYP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HYP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1A1:N-[7-(1H-IMIDAZOL-1-YL)-2-(PYRIDIN-3-YL)[1,3]THIAZOLO[5,4-D]PYRIMIDIN-5-YL]CYCLOPROPANECARBOXAMIDE'>1A1</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1A1:N-[7-(1H-IMIDAZOL-1-YL)-2-(PYRIDIN-3-YL)[1,3]THIAZOLO[5,4-D]PYRIMIDIN-5-YL]CYCLOPROPANECARBOXAMIDE'>1A1</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hym|4hym]], [[4hy1|4hy1]], [[4hz0|4hz0]], [[4hz5|4hz5]], [[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=4hyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hyp OCA], [https://pdbe.org/4hyp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hyp RCSB], [https://www.ebi.ac.uk/pdbsum/4hyp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hyp ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">acrB, b3699, gyrB, himB, hisU, JW5625, nalC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</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=4hyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hyp OCA], [http://pdbe.org/4hyp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hyp RCSB], [http://www.ebi.ac.uk/pdbsum/4hyp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hyp ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GYRB_ECOLI GYRB_ECOLI]] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.<ref>PMID:12051843</ref> <ref>PMID:18642932</ref> <ref>PMID:20675723</ref>
+[https://www.uniprot.org/uniprot/GYRB_ECOLI GYRB_ECOLI] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.<ref>PMID:12051843</ref> <ref>PMID:18642932</ref> <ref>PMID:20675723</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 20: @@
 ==See Also==
-*[[Gyrase|Gyrase]]
+*[[Gyrase 3D Structures|Gyrase 3D Structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Ecoli]]
+[[Category: Escherichia coli K-12]]
-[[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: Gyrase]]
-[[Category: Gyrb]]
-[[Category: Isomerase-isomerase inhibitor complex]]
-[[Category: Nucleotide-binding]]
-[[Category: Topoisomerase]]

4hyp: Difference between revisions

Revision as of 08:27, 9 November 2022

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.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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