8cc2: Difference between revisions
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==Cathepsin B1 from Schistosoma mansoni in complex with gallinamide A== | ==Cathepsin B1 from Schistosoma mansoni in complex with gallinamide A== | ||
<StructureSection load='8cc2' size='340' side='right'caption='[[8cc2]]' scene=''> | <StructureSection load='8cc2' size='340' side='right'caption='[[8cc2]], [[Resolution|resolution]] 1.20Å' 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=8CC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CC2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8cc2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Schistosoma_mansoni Schistosoma mansoni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CC2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CC2 FirstGlance]. <br> | ||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction</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]] 1.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GN9:gallinamide+A,+bound+form'>GN9</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=8cc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cc2 OCA], [https://pdbe.org/8cc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cc2 RCSB], [https://www.ebi.ac.uk/pdbsum/8cc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cc2 ProSAT]</span></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=8cc2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cc2 OCA], [https://pdbe.org/8cc2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cc2 RCSB], [https://www.ebi.ac.uk/pdbsum/8cc2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cc2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/Q8MNY2_SCHMA Q8MNY2_SCHMA] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics. | |||
Nature-Inspired Gallinamides Are Potent Antischistosomal Agents: Inhibition of the Cathepsin B1 Protease Target and Binding Mode Analysis.,Spiwokova P, Horn M, Fanfrlik J, Jilkova A, Fajtova P, Leontovyc A, Houstecka R, Bielikova L, Brynda J, Chanova M, Mertlikova-Kaiserova H, Caro-Diaz EJE, Almaliti J, El-Sakkary N, Gerwick WH, Caffrey CR, Mares M ACS Infect Dis. 2024 Jun 14;10(6):1935-1948. doi: 10.1021/acsinfecdis.3c00589. , Epub 2024 May 17. PMID:38757505<ref>PMID:38757505</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8cc2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Schistosoma mansoni]] | ||
[[Category: Brynda J]] | |||
[[Category: Gerwick WH]] | |||
[[Category: Mares M]] | |||
[[Category: Rubesova P]] | |||
Latest revision as of 08:47, 7 August 2024
Cathepsin B1 from Schistosoma mansoni in complex with gallinamide ACathepsin B1 from Schistosoma mansoni in complex with gallinamide A
Structural highlights
FunctionPublication Abstract from PubMedSchistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics. Nature-Inspired Gallinamides Are Potent Antischistosomal Agents: Inhibition of the Cathepsin B1 Protease Target and Binding Mode Analysis.,Spiwokova P, Horn M, Fanfrlik J, Jilkova A, Fajtova P, Leontovyc A, Houstecka R, Bielikova L, Brynda J, Chanova M, Mertlikova-Kaiserova H, Caro-Diaz EJE, Almaliti J, El-Sakkary N, Gerwick WH, Caffrey CR, Mares M ACS Infect Dis. 2024 Jun 14;10(6):1935-1948. doi: 10.1021/acsinfecdis.3c00589. , Epub 2024 May 17. PMID:38757505[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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