8a4x: Difference between revisions
New page: '''Unreleased structure''' The entry 8a4x is ON HOLD Authors: Description: Category: Unreleased Structures |
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==Crystal structure of human Cathepsin L with covalently bound Calpain inhibitor III== | |||
<StructureSection load='8a4x' size='340' side='right'caption='[[8a4x]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8a4x]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8A4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A4X 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=L3F:(phenylmethyl)+~{N}-[(2~{S})-3-methyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanyl-3-phenyl-propan-2-yl]amino]butan-2-yl]carbamate'>L3F</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=8a4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a4x OCA], [https://pdbe.org/8a4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a4x RCSB], [https://www.ebi.ac.uk/pdbsum/8a4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a4x ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CATL1_HUMAN CATL1_HUMAN] Important for the overall degradation of proteins in lysosomes. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due to ubiquitous expression, cathepsin L (CatL) is considered a promising drug target in the context of different viral and lysosome-related diseases. We characterized the anti-SARS-CoV-2 activity of a set of carbonyl- and succinyl epoxide-based inhibitors, which were previously identified as inhibitors of cathepsins or related cysteine proteases. Calpain inhibitor XII, MG-101, and CatL inhibitor IV possess antiviral activity in the very low nanomolar EC(50) range in Vero E6 cells and inhibit CatL in the picomolar K(i) range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease alpha-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 A present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development. | |||
Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.,Falke S, Lieske J, Herrmann A, Loboda J, Karnicar K, Gunther S, Reinke PYA, Ewert W, Usenik A, Lindic N, Sekirnik A, Dretnik K, Tsuge H, Turk V, Chapman HN, Hinrichs W, Ebert G, Turk D, Meents A J Med Chem. 2024 May 9;67(9):7048-7067. doi: 10.1021/acs.jmedchem.3c02351. Epub , 2024 Apr 17. PMID:38630165<ref>PMID:38630165</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8a4x" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chapman HN]] | |||
[[Category: Ewert W]] | |||
[[Category: Falke S]] | |||
[[Category: Guenther S]] | |||
[[Category: Hinrichs W]] | |||
[[Category: Karnicar K]] | |||
[[Category: Lieske J]] | |||
[[Category: Lindic N]] | |||
[[Category: Loboda J]] | |||
[[Category: Meents A]] | |||
[[Category: Reinke PYA]] | |||
[[Category: Sekirnik A]] | |||
[[Category: Turk D]] | |||
[[Category: Usenik A]] | |||
Latest revision as of 14:51, 23 October 2024
Crystal structure of human Cathepsin L with covalently bound Calpain inhibitor IIICrystal structure of human Cathepsin L with covalently bound Calpain inhibitor III
Structural highlights
FunctionCATL1_HUMAN Important for the overall degradation of proteins in lysosomes. Publication Abstract from PubMedEmerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due to ubiquitous expression, cathepsin L (CatL) is considered a promising drug target in the context of different viral and lysosome-related diseases. We characterized the anti-SARS-CoV-2 activity of a set of carbonyl- and succinyl epoxide-based inhibitors, which were previously identified as inhibitors of cathepsins or related cysteine proteases. Calpain inhibitor XII, MG-101, and CatL inhibitor IV possess antiviral activity in the very low nanomolar EC(50) range in Vero E6 cells and inhibit CatL in the picomolar K(i) range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease alpha-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 A present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development. Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors.,Falke S, Lieske J, Herrmann A, Loboda J, Karnicar K, Gunther S, Reinke PYA, Ewert W, Usenik A, Lindic N, Sekirnik A, Dretnik K, Tsuge H, Turk V, Chapman HN, Hinrichs W, Ebert G, Turk D, Meents A J Med Chem. 2024 May 9;67(9):7048-7067. doi: 10.1021/acs.jmedchem.3c02351. Epub , 2024 Apr 17. PMID:38630165[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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