5npk: Difference between revisions
m Protected "5npk" [edit=sysop:move=sysop] |
No edit summary |
||
| (2 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==1.98A STRUCTURE OF THIOPHENE1 WITH S.AUREUS DNA GYRASE AND DNA== | |||
<StructureSection load='5npk' size='340' side='right'caption='[[5npk]], [[Resolution|resolution]] 1.98Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5npk]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_N315 Staphylococcus aureus subsp. aureus N315] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NPK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NPK FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.98Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=94H:~{N}-[(1~{R})-2-azanyl-1-phenyl-ethyl]-4-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)thiophene-2-carboxamide'>94H</scene>, <scene name='pdbligand=9JN:~{N}-[(1~{S})-2-azanyl-1-phenyl-ethyl]-4-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)thiophene-2-carboxamide'>9JN</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=5npk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5npk OCA], [https://pdbe.org/5npk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5npk RCSB], [https://www.ebi.ac.uk/pdbsum/5npk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5npk ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GYRA_STAAN GYRA_STAAN] 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.[HAMAP-Rule:MF_01897][https://www.uniprot.org/uniprot/GYRB_STAAN GYRB_STAAN] 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 (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development. | |||
Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.,Chan PF, Germe T, Bax BD, Huang J, Thalji RK, Bacque E, Checchia A, Chen D, Cui H, Ding X, Ingraham K, McCloskey L, Raha K, Srikannathasan V, Maxwell A, Stavenger RA Proc Natl Acad Sci U S A. 2017 May 30;114(22):E4492-E4500. doi:, 10.1073/pnas.1700721114. Epub 2017 May 15. PMID:28507124<ref>PMID:28507124</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Bax | <div class="pdbe-citations 5npk" style="background-color:#fffaf0;"></div> | ||
[[Category: Chan | |||
[[Category: Stavenger | ==See Also== | ||
*[[Gyrase 3D Structures|Gyrase 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus subsp. aureus N315]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Bax BD]] | |||
[[Category: Chan PF]] | |||
[[Category: Stavenger RA]] | |||
Latest revision as of 16:19, 15 November 2023
1.98A STRUCTURE OF THIOPHENE1 WITH S.AUREUS DNA GYRASE AND DNA1.98A STRUCTURE OF THIOPHENE1 WITH S.AUREUS DNA GYRASE AND DNA
Structural highlights
FunctionGYRA_STAAN 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.[HAMAP-Rule:MF_01897]GYRB_STAAN 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 (By similarity). Publication Abstract from PubMedA paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase-DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase.,Chan PF, Germe T, Bax BD, Huang J, Thalji RK, Bacque E, Checchia A, Chen D, Cui H, Ding X, Ingraham K, McCloskey L, Raha K, Srikannathasan V, Maxwell A, Stavenger RA Proc Natl Acad Sci U S A. 2017 May 30;114(22):E4492-E4500. doi:, 10.1073/pnas.1700721114. Epub 2017 May 15. PMID:28507124[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||