9shr: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 9shr is ~~ON HOLD until Paper~~ Publication

==Alpha-Hemolysin of S.aureus (monomer) in complex with the small molecule N-(3-(Diethylamino)propyl)-1-(6-(p-tolyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide==

== Structural highlights ==

<table><tr><td colspan='2'>[[9shr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SHR 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]] 2.08Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JN0:~{N}-[3-(diethylamino)propyl]-1-[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidine-4-carboxamide'>A1JN0</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=9shr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9shr OCA], [https://pdbe.org/9shr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9shr RCSB], [https://www.ebi.ac.uk/pdbsum/9shr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9shr ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/HLA_STAA8 HLA_STAA8] Alpha-toxin binds to the membrane of eukaryotic cells resulting in the release of low-molecular weight molecules and leading to an eventual osmotic lysis. Heptamer oligomerization and pore formation is required for lytic activity (By similarity).

== Publication Abstract from PubMed ==

Staphylococcus aureus is a major human pathogen responsible for severe infections that necessitate alternative therapeutic strategies. Its key virulence factor alpha-hemolysin (Hla) mediates host cell damage via pore formation, making it an attractive target for antivirulence interventions. Here, we report the development of a high-throughput cellular assay measuring toxin-induced calcium influx. Its application led to the identification of thiadiazole-based small molecule inhibitors of Hla. Structure-activity relationship studies with 18 analogs led to inhibitors with a cellular potency up to 5.4 microM. X-ray crystallography of Hla in complex with compound 1 revealed that the thiadiazole bound a hydrophobic pocket at the interface of the amino latch and prestem domains, exerting a dual mechanism that blocks stem loop unfolding as well as membrane attachment. These findings introduce thiadiazoles as a novel chemical class of antivirulence therapeutics against S. aureus infections.

~~Authors~~:

An Imidazo[2,1-b][1,3,4]thiadiazole Derivative Inhibits the Virulence Factor alpha-Hemolysin by Blocking the Pullout of Its Stem Domain.,Korotkov VS, Lukat P, Di Lucrezia R, Shekhar A, Degenhart C, Diestel R, Bilitewski U, Dinkel K, Blankenfeldt W, Bronstrup M ChemMedChem. 2026 Feb 25;21(4):e202501098. doi: 10.1002/cmdc.202501098. PMID:41725408<ref>PMID:41725408</ref>

~~Description~~:

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

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Large Structures]]

[[Category: Staphylococcus aureus]]

[[Category: Blankenfeldt W]]

[[Category: Broenstrup M]]

[[Category: Lukat P]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9shr is ON HOLD  until Paper Publication
+==Alpha-Hemolysin of S.aureus (monomer) in complex with the small molecule N-(3-(Diethylamino)propyl)-1-(6-(p-tolyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide==
+<StructureSection load='9shr' size='340' side='right'caption='[[9shr]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9shr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SHR 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]] 2.08&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JN0:~{N}-[3-(diethylamino)propyl]-1-[6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]piperidine-4-carboxamide'>A1JN0</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=9shr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9shr OCA], [https://pdbe.org/9shr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9shr RCSB], [https://www.ebi.ac.uk/pdbsum/9shr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9shr ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/HLA_STAA8 HLA_STAA8] Alpha-toxin binds to the membrane of eukaryotic cells resulting in the release of low-molecular weight molecules and leading to an eventual osmotic lysis. Heptamer oligomerization and pore formation is required for lytic activity (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Staphylococcus aureus is a major human pathogen responsible for severe infections that necessitate alternative therapeutic strategies. Its key virulence factor alpha-hemolysin (Hla) mediates host cell damage via pore formation, making it an attractive target for antivirulence interventions. Here, we report the development of a high-throughput cellular assay measuring toxin-induced calcium influx. Its application led to the identification of thiadiazole-based small molecule inhibitors of Hla. Structure-activity relationship studies with 18 analogs led to inhibitors with a cellular potency up to 5.4 microM. X-ray crystallography of Hla in complex with compound 1 revealed that the thiadiazole bound a hydrophobic pocket at the interface of the amino latch and prestem domains, exerting a dual mechanism that blocks stem loop unfolding as well as membrane attachment. These findings introduce thiadiazoles as a novel chemical class of antivirulence therapeutics against S. aureus infections.
-Authors:
+An Imidazo[2,1-b][1,3,4]thiadiazole Derivative Inhibits the Virulence Factor alpha-Hemolysin by Blocking the Pullout of Its Stem Domain.,Korotkov VS, Lukat P, Di Lucrezia R, Shekhar A, Degenhart C, Diestel R, Bilitewski U, Dinkel K, Blankenfeldt W, Bronstrup M ChemMedChem. 2026 Feb 25;21(4):e202501098. doi: 10.1002/cmdc.202501098. PMID:41725408<ref>PMID:41725408</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9shr" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Staphylococcus aureus]]
+[[Category: Blankenfeldt W]]
+[[Category: Broenstrup M]]
+[[Category: Lukat P]]