3s3q: Difference between revisions
New page: '''Unreleased structure''' The entry 3s3q is ON HOLD Authors: Rezacova, P., Jilkova, A., Brynda, J., Horn, M., Mares, M. Description: Structure of cathepsin B1 from Schistosoma mansoni... |
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==Structure of cathepsin B1 from Schistosoma mansoni in complex with K11017 inhibitor== | |||
<StructureSection load='3s3q' size='340' side='right'caption='[[3s3q]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3s3q]] 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=3S3Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3Q 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]] 1.8Å</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=C1P:N~2~-(MORPHOLIN-4-YLCARBONYL)-N-[(3S)-1-PHENYL-5-(PHENYLSULFONYL)PENTAN-3-YL]-L-LEUCINAMIDE'>C1P</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=3s3q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3q OCA], [https://pdbe.org/3s3q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3q RCSB], [https://www.ebi.ac.uk/pdbsum/3s3q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3q ProSAT]</span></td></tr> | |||
</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 afflicts over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated peptidase that digests host blood proteins as a source of nutrients. It is under investigation as a drug target. To further this goal, we report three crystal structures of SmCB1 complexed with peptidomimetic inhibitors as follows: the epoxide CA074 at 1.3 A resolution and the vinyl sulfones K11017 and K11777 at 1.8 and 2.5 A resolutions, respectively. Interactions of the inhibitors with the subsites of the active-site cleft were evaluated by quantum chemical calculations. These data and inhibition profiling with a panel of vinyl sulfone derivatives identify key binding interactions and provide insight into the specificity of SmCB1 inhibition. Furthermore, hydrolysis profiling of SmCB1 using synthetic peptides and the natural substrate hemoglobin revealed that carboxydipeptidase activity predominates over endopeptidolysis, thereby demonstrating the contribution of the occluding loop that restricts access to the active-site cleft. Critically, the severity of phenotypes induced in the parasite by vinyl sulfone inhibitors correlated with enzyme inhibition, providing support that SmCB1 is a valuable drug target. The present structure and inhibitor interaction data provide a footing for the rational design of anti-schistosomal inhibitors. | |||
Structural Basis for Inhibition of Cathepsin B Drug Target from the Human Blood Fluke, Schistosoma mansoni.,Jilkova A, Rezacova P, Lepsik M, Horn M, Vachova J, Fanfrlik J, Brynda J, McKerrow JH, Caffrey CR, Mares M J Biol Chem. 2011 Oct 14;286(41):35770-81. Epub 2011 Aug 10. PMID:21832058<ref>PMID:21832058</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3s3q" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cathepsin 3D structures|Cathepsin 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Schistosoma mansoni]] | |||
[[Category: Brynda J]] | |||
[[Category: Horn M]] | |||
[[Category: Jilkova A]] | |||
[[Category: Mares M]] | |||
[[Category: Rezacova P]] | |||
Latest revision as of 12:40, 30 October 2024
Structure of cathepsin B1 from Schistosoma mansoni in complex with K11017 inhibitorStructure of cathepsin B1 from Schistosoma mansoni in complex with K11017 inhibitor
Structural highlights
FunctionPublication Abstract from PubMedSchistosomiasis caused by a parasitic blood fluke of the genus Schistosoma afflicts over 200 million people worldwide. Schistosoma mansoni cathepsin B1 (SmCB1) is a gut-associated peptidase that digests host blood proteins as a source of nutrients. It is under investigation as a drug target. To further this goal, we report three crystal structures of SmCB1 complexed with peptidomimetic inhibitors as follows: the epoxide CA074 at 1.3 A resolution and the vinyl sulfones K11017 and K11777 at 1.8 and 2.5 A resolutions, respectively. Interactions of the inhibitors with the subsites of the active-site cleft were evaluated by quantum chemical calculations. These data and inhibition profiling with a panel of vinyl sulfone derivatives identify key binding interactions and provide insight into the specificity of SmCB1 inhibition. Furthermore, hydrolysis profiling of SmCB1 using synthetic peptides and the natural substrate hemoglobin revealed that carboxydipeptidase activity predominates over endopeptidolysis, thereby demonstrating the contribution of the occluding loop that restricts access to the active-site cleft. Critically, the severity of phenotypes induced in the parasite by vinyl sulfone inhibitors correlated with enzyme inhibition, providing support that SmCB1 is a valuable drug target. The present structure and inhibitor interaction data provide a footing for the rational design of anti-schistosomal inhibitors. Structural Basis for Inhibition of Cathepsin B Drug Target from the Human Blood Fluke, Schistosoma mansoni.,Jilkova A, Rezacova P, Lepsik M, Horn M, Vachova J, Fanfrlik J, Brynda J, McKerrow JH, Caffrey CR, Mares M J Biol Chem. 2011 Oct 14;286(41):35770-81. Epub 2011 Aug 10. PMID:21832058[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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