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| | <StructureSection load='5z9l' size='340' side='right'caption='[[5z9l]], [[Resolution|resolution]] 1.60Å' scene=''> | | <StructureSection load='5z9l' size='340' side='right'caption='[[5z9l]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5z9l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Z9L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5Z9L FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5z9l]] is a 2 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=5Z9L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5Z9L FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8H8:2-FLUORO-4-HYDROXYBENZONITRILE'>8H8</scene>, <scene name='pdbligand=AX7:1H-BENZIMIDAZOL-2-AMINE'>AX7</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8H8:2-FLUORO-4-HYDROXYBENZONITRILE'>8H8</scene>, <scene name='pdbligand=AX7:1H-BENZIMIDAZOL-2-AMINE'>AX7</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5z9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5z9l OCA], [http://pdbe.org/5z9l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5z9l RCSB], [http://www.ebi.ac.uk/pdbsum/5z9l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5z9l ProSAT]</span></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=5z9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5z9l OCA], [https://pdbe.org/5z9l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5z9l RCSB], [https://www.ebi.ac.uk/pdbsum/5z9l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5z9l ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | *[[Gyrase 3D Structures|Gyrase 3D Structures]] | | *[[Gyrase 3D Structures|Gyrase 3D Structures]] |
| - | *[[Topoisomerase 3D structures|Topoisomerase 3D structures]] | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Escherichia coli K-12]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Huang, X]] | + | [[Category: Huang X]] |
| - | [[Category: Zhou, H]] | + | [[Category: Zhou H]] |
| - | [[Category: Antibacterial]]
| + | |
| - | [[Category: Dna topoisomerase]]
| + | |
| - | [[Category: Drug target]]
| + | |
| - | [[Category: Fragment-base lead discovery]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| Structural highlights
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
Discovery of new drug binding sites on well-established targets is of great interest as it facilitates the design of new mechanistic inhibitors to overcome the acquired drug resistance. Small chemical fragments can easily enter and bind to the cavities on the protein surface. Thus, they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and both its GyrA and GyrB subunits are clinically validated antibacterial targets. New mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by the FDA due to its reduced efficiency and other reasons. Here, a fragment library was screened against the E. coli GyrB ATPase domain by combining affinity- and bioactivity-based approaches. The following X-ray crystallographic efforts were made to determine the cocrystal structures of GyrB with ten fragment hits, and three different binding modes were disclosed. Fortunately, a hydrophobic pocket which is previously unknown was identified by two fragments. Fragments that bind to this pocket were shown to inhibit the ATPase activity as well as the DNA topological transition activity of DNA gyrase in vitro. A set of fragment analogs were screened to explore the binding capacity of this pocket and identify the better starting fragments for lead development. Phylogenetic analysis revealed that this pocket is conserved in most Gram-negative and also many Gram-positive human pathogenic bacteria, implying a broad-spectrum antibacterial potential and a lower risk of mutation. Thus, the novel druggable pocket and the starting fragments provide a novel basis for designing new GyrB-targeting therapeutics.
Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes.,Huang X, Guo J, Liu Q, Gu Q, Xu J, Zhou H Medchemcomm. 2018 Jul 4;9(10):1619-1629. doi: 10.1039/c8md00148k. eCollection, 2018 Oct 1. PMID:30429968[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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:http://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:http://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
- ↑ Huang X, Guo J, Liu Q, Gu Q, Xu J, Zhou H. Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes. Medchemcomm. 2018 Jul 4;9(10):1619-1629. doi: 10.1039/c8md00148k. eCollection, 2018 Oct 1. PMID:30429968 doi:http://dx.doi.org/10.1039/c8md00148k
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