8B5F

Human cathepsin B in complex with the carbamate inhibitor 31

Summary for 8B5F

• Entry DOI: 10.2210/pdb8b5f/pdb
• Descriptor: Cathepsin B, (2S)-2-[[(2S)-2-[[3-chloranyl-4-[[3-phenyl-2-(phenylmethyl)propanoyl]amino]phenoxy]carbonylamino]-3-cyclohexyl-propanoyl]amino]-3-phenyl-propanoic acid, 1,2-ETHANEDIOL, ... (4 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: 28728.48

Authors

Rubesova, P.,Guetschow, M.,Mares, M. (deposition date: 2022-09-22, 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

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: 40394881
DOI: 10.1002/anie.202506832

Experimental method

X-RAY DIFFRACTION (1.7 Å)