7QBL

Structure of cathepsin K in complex with the 3-cyano-3-aza-beta-amino acid inhibitor Gu2602

Summary for 7QBL

• Entry DOI: 10.2210/pdb7qbl/pdb
• Descriptor: Cathepsin K, ~{tert}-butyl ~{N}-[iminomethyl-[2-[methyl-(phenylmethyl)amino]-2-oxidanylidene-ethyl]amino]carbamate (3 entities in total)
• Functional Keywords: cathepsin k, protease inhibitor, cyanohydrazide warhead, azadipeptide nitrile, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 23843.87

Authors

Benysek, J.,Busa, M.,Mares, M. (deposition date: 2021-11-19, release date: 2022-01-26, Last modification date: 2024-10-16)

Primary citation

Benysek, J.,Busa, M.,Rubesova, P.,Fanfrlik, J.,Lepsik, M.,Brynda, J.,Matouskova, Z.,Bartz, U.,Horn, M.,Gutschow, M.,Mares, M.
Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes.
J Enzyme Inhib Med Chem, 37:515-526, 2022

PubMed Abstract: Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile and a 3-cyano-3-aza-β-amino acid . Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

PubMed: 35144520
DOI: 10.1080/14756366.2021.2024527

Experimental method

X-RAY DIFFRACTION (2 Å)