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==Structure of cathepsin B1 from Schistosoma mansoni (SmCB1) in complex with an azanitrile inhibitor== | ==Structure of cathepsin B1 from Schistosoma mansoni (SmCB1) in complex with an azanitrile inhibitor== | ||
<StructureSection load='6yi7' size='340' side='right'caption='[[6yi7]]' scene=''> | <StructureSection load='6yi7' size='340' side='right'caption='[[6yi7]], [[Resolution|resolution]] 1.29Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YI7 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6yi7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Blood_fluke Blood fluke]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YI7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YI7 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </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=ORW:1-[(2~{S})-1-[[iminomethyl(methyl)amino]-methyl-amino]-4-methyl-1-oxidanylidene-pentan-2-yl]-3-(phenylmethyl)urea'>ORW</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3s3q|3s3q]], [[3s3r|3s3r]], [[3qsd|3qsd]], [[5ogr|5ogr]], [[5ogq|5ogq]], [[4i07|4i07]], [[4i05|4i05]], [[4i04|4i04]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">cb1.1, Smp_103610 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=6183 Blood fluke])</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=6yi7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yi7 OCA], [https://pdbe.org/6yi7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yi7 RCSB], [https://www.ebi.ac.uk/pdbsum/6yi7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yi7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni, a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from E- to Z-configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis. | |||
Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni: Structural and Mechanistic Insights into Chemotype Reactivity.,Jilkova A, Horn M, Fanfrlik J, Kuppers J, Pachl P, Rezacova P, Lepsik M, Fajtova P, Rubesova P, Chanova M, Caffrey CR, Gutschow M, Mares M ACS Infect Dis. 2021 Jan 8;7(1):189-201. doi: 10.1021/acsinfecdis.0c00644. Epub, 2020 Dec 10. PMID:33301315<ref>PMID:33301315</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yi7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Blood fluke]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Fanfrlik J]] | [[Category: Fanfrlik, J]] | ||
[[Category: Guetschow M]] | [[Category: Guetschow, M]] | ||
[[Category: Jilkova A]] | [[Category: Jilkova, A]] | ||
[[Category: Mares M]] | [[Category: Mares, M]] | ||
[[Category: Pachl P]] | [[Category: Pachl, P]] | ||
[[Category: Rezacova P]] | [[Category: Rezacova, P]] | ||
[[Category: Rubesova P]] | [[Category: Rubesova, P]] | ||
[[Category: Azanitrile]] | |||
[[Category: Cysteine protease]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Parasite]] | |||
Revision as of 08:48, 6 October 2021
Structure of cathepsin B1 from Schistosoma mansoni (SmCB1) in complex with an azanitrile inhibitorStructure of cathepsin B1 from Schistosoma mansoni (SmCB1) in complex with an azanitrile inhibitor
Structural highlights
Publication Abstract from PubMedAzapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni, a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from E- to Z-configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis. Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni: Structural and Mechanistic Insights into Chemotype Reactivity.,Jilkova A, Horn M, Fanfrlik J, Kuppers J, Pachl P, Rezacova P, Lepsik M, Fajtova P, Rubesova P, Chanova M, Caffrey CR, Gutschow M, Mares M ACS Infect Dis. 2021 Jan 8;7(1):189-201. doi: 10.1021/acsinfecdis.0c00644. Epub, 2020 Dec 10. PMID:33301315[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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