8a4v

Crystal structure of human cathepsin L with covalently bound E-64

spinqualitylabelsall models 8a4v, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8a4v is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.65Å Ligands: DMS, E64, PEG, PGE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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