8B4T
Human cathepsin B in complex with the carbamate inhibitor 7
Summary for 8B4T
| Entry DOI | 10.2210/pdb8b4t/pdb |
| Descriptor | Cathepsin B, (2S)-2-[[(2S)-2-[(4-chloranylphenoxy)carbonylamino]-3-cyclohexyl-propanoyl]amino]-3-phenyl-propanoic acid (3 entities in total) |
| Functional Keywords | cathepsin b cysteine cathepsin inhibitor carbamate peptidomimetic cysteine proteinases, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 28429.12 |
| Authors | Rubesova, P.,Guetschow, M.,Mares, M. (deposition date: 2022-09-21, release date: 2023-10-04, Last modification date: 2025-08-27) |
| Primary citation | Breuer, C.,Kuppers, J.,Schulz-Fincke, A.C.,Heilos, A.,Lemke, C.,Spiwokova, P.,Schmitz, J.,Cremer, L.,Frigole-Vivas, M.,Lulsdorff, M.,Mertens, M.D.,Wichterle, F.,Apeltauer, M.,Horn, M.,Gilberg, E.,Furtmann, N.,Bajorath, J.,Bartz, U.,Engels, B.,Mares, M.,Gutschow, M. Redirecting the Peptide Cleavage Causes Protease Inactivation. Angew.Chem.Int.Ed.Engl., 64:e202506832-e202506832, 2025 Cited by PubMed Abstract: Cysteine and serine proteases cleave peptides through covalent catalysis by generating a transient adduct with the N-terminal part of the substrate after releasing its C-terminal part. We demonstrate the unique redirection of this event leading to strong enzyme inactivation. For targeting human cathepsin B, a cysteine protease of significant therapeutic importance, we designed tailored peptidomimetics with a variety of dipeptide fragments directed toward the occluding loop and equipped with numerous N-terminal carbamate warheads. The carbamate deprotonation catalyzed by the active site thiolate initiates the redirected cleavage. The C-terminal part of the inhibitors remains covalently attached to the protease. Hydrolysis of such carbamoyl-enzyme complexes is catalytically unsupported rendering inhibition irreversible. This novel mechanism of action comprises a significant extension of the covalent drug space. PubMed: 40394881DOI: 10.1002/anie.202506832 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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