|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6y8o' size='340' side='right'caption='[[6y8o]], [[Resolution|resolution]] 1.60Å' scene=''> | | <StructureSection load='6y8o' size='340' side='right'caption='[[6y8o]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6y8o]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_smegmatis"_trevisan_1889 "bacillus smegmatis" trevisan 1889]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y8O OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y8O FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6y8o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis Mycolicibacterium smegmatis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y8O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Y8O FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NOV:NOVOBIOCIN'>NOV</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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6y8l|6y8l]], [[6y8n|6y8n]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NOV:NOVOBIOCIN'>NOV</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gyrB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1772 "Bacillus smegmatis" Trevisan 1889])</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=6y8o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y8o OCA], [https://pdbe.org/6y8o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6y8o RCSB], [https://www.ebi.ac.uk/pdbsum/6y8o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6y8o ProSAT]</span></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 DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.6.2.2 5.6.2.2] </span></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=6y8o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y8o OCA], [http://pdbe.org/6y8o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y8o RCSB], [http://www.ebi.ac.uk/pdbsum/6y8o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y8o ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GYRB_MYCSM GYRB_MYCSM]] 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. | + | [https://www.uniprot.org/uniprot/GYRB_MYCS2 GYRB_MYCS2] A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner (PubMed:8878580) to modulate DNA topology and maintain chromosomes in an underwound state. Negative supercoiling favors strand separation, and DNA replication, transcription, recombination and repair, all of which involve strand separation. Also able to catalyze the interconversion of other topological isomers of dsDNA rings, including catenanes and knotted rings. Type II topoisomerases break and join 2 DNA strands simultaneously in an ATP-dependent manner.[HAMAP-Rule:MF_01898]<ref>PMID:8878580</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6y8o" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6y8o" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Gyrase 3D Structures|Gyrase 3D Structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus smegmatis trevisan 1889]] | |
| - | [[Category: DNA topoisomerase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Charrier, C]] | + | [[Category: Mycolicibacterium smegmatis]] |
| - | [[Category: Cooper, I R]] | + | [[Category: Charrier C]] |
| - | [[Category: Henderson, S R]] | + | [[Category: Cooper IR]] |
| - | [[Category: Lawson, D M]] | + | [[Category: Henderson SR]] |
| - | [[Category: Malone, B]] | + | [[Category: Lawson DM]] |
| - | [[Category: Maxwell, A]] | + | [[Category: Malone B]] |
| - | [[Category: McGarry, D H]] | + | [[Category: Maxwell A]] |
| - | [[Category: Mitchenall, L A]] | + | [[Category: McGarry DH]] |
| - | [[Category: Pichowicz, M]] | + | [[Category: Mitchenall LA]] |
| - | [[Category: Salisbury, A]] | + | [[Category: Pichowicz M]] |
| - | [[Category: Stevenson, C E.M]] | + | [[Category: Salisbury A]] |
| - | [[Category: Zholnerovych, Y]] | + | [[Category: Stevenson CEM]] |
| - | [[Category: Binding site]]
| + | [[Category: Zholnerovych Y]] |
| - | [[Category: Dna binding protein]]
| + | |
| - | [[Category: Dna gyrase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Isomerase]]
| + | |
| - | [[Category: Novobiocin iv]]
| + | |
| Structural highlights
Function
GYRB_MYCS2 A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner (PubMed:8878580) to modulate DNA topology and maintain chromosomes in an underwound state. Negative supercoiling favors strand separation, and DNA replication, transcription, recombination and repair, all of which involve strand separation. Also able to catalyze the interconversion of other topological isomers of dsDNA rings, including catenanes and knotted rings. Type II topoisomerases break and join 2 DNA strands simultaneously in an ATP-dependent manner.[HAMAP-Rule:MF_01898][1]
Publication Abstract from PubMed
OBJECTIVES: To evaluate the efficacy of two novel compounds against mycobacteria and determine the molecular basis of their action on DNA gyrase using structural and mechanistic approaches. METHODS: Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallography was used to determine the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863. RESULTS: Both compounds, Redx03863 and Redx04739, were active against selected Gram-positive and Gram-negative species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compounds were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive. CONCLUSIONS: Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compounds could have potential to be further exploited as antibiotics.
Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase.,Henderson SR, Stevenson CEM, Malone B, Zholnerovych Y, Mitchenall LA, Pichowicz M, McGarry DH, Cooper IR, Charrier C, Salisbury AM, Lawson DM, Maxwell A J Antimicrob Chemother. 2020 Jul 30. pii: 5878045. doi: 10.1093/jac/dkaa286. PMID:32728686[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Revel-Viravau V, Truong QC, Moreau N, Jarlier V, Sougakoff W. Sequence analysis, purification, and study of inhibition by 4-quinolones of the DNA gyrase from Mycobacterium smegmatis. Antimicrob Agents Chemother. 1996 Sep;40(9):2054-61. PMID:8878580
- ↑ Henderson SR, Stevenson CEM, Malone B, Zholnerovych Y, Mitchenall LA, Pichowicz M, McGarry DH, Cooper IR, Charrier C, Salisbury AM, Lawson DM, Maxwell A. Structural and mechanistic analysis of ATPase inhibitors targeting mycobacterial DNA gyrase. J Antimicrob Chemother. 2020 Jul 30. pii: 5878045. doi: 10.1093/jac/dkaa286. PMID:32728686 doi:http://dx.doi.org/10.1093/jac/dkaa286
|
