6f8b: Difference between revisions
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The | ==LasB bound to thiol based inhibitor== | ||
<StructureSection load='6f8b' size='340' side='right' caption='[[6f8b]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f8b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F8B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F8B FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CXH:~{N}-(3,4-dichlorophenyl)-2-sulfanyl-ethanamide'>CXH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pseudolysin Pseudolysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.26 3.4.24.26] </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=6f8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f8b OCA], [http://pdbe.org/6f8b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f8b RCSB], [http://www.ebi.ac.uk/pdbsum/6f8b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f8b ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs). | |||
Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.,Kany AM, Sikandar A, Haupenthal J, Yahiaoui S, Maurer CK, Proschak E, Kohnke J, Hartmann RW ACS Infect Dis. 2018 Mar 6. doi: 10.1021/acsinfecdis.8b00010. PMID:29485268<ref>PMID:29485268</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6f8b" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Pseudolysin]] | |||
[[Category: Koehnke, J]] | |||
[[Category: Sikandar, A]] | [[Category: Sikandar, A]] | ||
[[Category: | [[Category: Hydrolase]] | ||
[[Category: Inhibitor]] | |||
[[Category: Lasb]] | |||
Revision as of 09:41, 28 March 2018
LasB bound to thiol based inhibitorLasB bound to thiol based inhibitor
Structural highlights
Publication Abstract from PubMedThe increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs). Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.,Kany AM, Sikandar A, Haupenthal J, Yahiaoui S, Maurer CK, Proschak E, Kohnke J, Hartmann RW ACS Infect Dis. 2018 Mar 6. doi: 10.1021/acsinfecdis.8b00010. PMID:29485268[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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