8OFA
Crystal structure of human cathepsin L interacting with tosyl phenylalanyl chloromethyl ketone (TPCK)
Summary for 8OFA
| Entry DOI | 10.2210/pdb8ofa/pdb |
| Related | 7ZS7 8A5B 8AHV 8B4F 8C77 |
| Descriptor | Cathepsin L, N-[(2S)-4-chloro-3-oxo-1-phenyl-butan-2-yl]-4-methyl-benzenesulfonamide, 1,2-ETHANEDIOL, ... (10 entities in total) |
| Functional Keywords | cystein protease, drug target, lysosome, virus cell entry, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 101289.20 |
| Authors | Falke, S.,Lieske, J.,Guenther, S.,Ewert, W.,Reinke, P.Y.A.,Loboda, J.,Karnicar, K.,Usenik, A.,Lindic, N.,Sekirnik, A.,Chapman, H.N.,Hinrichs, W.,Turk, D.,Meents, A. (deposition date: 2023-03-14, release date: 2023-11-29, Last modification date: 2024-05-22) |
| Primary citation | Falke, S.,Lieske, J.,Herrmann, A.,Loboda, J.,Karnicar, K.,Gunther, S.,Reinke, P.Y.A.,Ewert, W.,Usenik, A.,Lindic, N.,Sekirnik, A.,Dretnik, K.,Tsuge, H.,Turk, V.,Chapman, H.N.,Hinrichs, W.,Ebert, G.,Turk, D.,Meents, A. Structural Elucidation and Antiviral Activity of Covalent Cathepsin L Inhibitors. J.Med.Chem., 67:7048-7067, 2024 Cited by PubMed Abstract: 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 range in Vero E6 cells and inhibit CatL in the picomolar range. We show a relevant off-target effect of CatL inhibition by the coronavirus main protease α-ketoamide inhibitor 13b. Crystal structures of CatL in complex with 14 compounds at resolutions better than 2 Å present a solid basis for structure-guided understanding and optimization of CatL inhibitors toward protease drug development. PubMed: 38630165DOI: 10.1021/acs.jmedchem.3c02351 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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