1AYV

CRYSTAL STRUCTURE OF CYSTEINE PROTEASE HUMAN CATHEPSIN K IN COMPLEX WITH A COVALENT THIAZOLHYDRAZIDE INHIBITOR

Summary for 1AYV

• Entry DOI: 10.2210/pdb1ayv/pdb
• Descriptor: CATHEPSIN K, N-[2-[1-(N-BENZYLOXYCARBONYLAMINO)-3-METHYLBUTYL]THIAZOL-4-YLCARBONYL]-N'-(BENZYLOXYCARBONYL-L-LEUCINYL)HYDRAZIDE (3 entities in total)
• Functional Keywords: hydrolase, sulfhydryl proteinase
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P43235
• Total number of polymer chains: 1
• Total formula weight: 24133.22

Authors

Zhao, B.,Smith, W.W.,Janson, C.A.,Abdel-Meguid, S.S. (deposition date: 1997-11-10, release date: 1998-11-25, Last modification date: 2024-10-23)

Primary citation

Thompson, S.K.,Halbert, S.M.,Bossard, M.J.,Tomaszek, T.A.,Levy, M.A.,Zhao, B.,Smith, W.W.,Abdel-Meguid, S.S.,Janson, C.A.,D'Alessio, K.J.,McQueney, M.S.,Amegadzie, B.Y.,Hanning, C.R.,DesJarlais, R.L.,Briand, J.,Sarkar, S.K.,Huddleston, M.J.,Ijames, C.F.,Carr, S.A.,Garnes, K.T.,Shu, A.,Heys, J.R.,Bradbeer, J.,Zembryki, D.,Lee-Rykaczewski, L.,James, I.E.,Lark, M.W.,Drake, F.H.,Gowen, M.,Gleason, J.G.,Veber, D.F.
Design of potent and selective human cathepsin K inhibitors that span the active site.
Proc.Natl.Acad.Sci.USA, 94:14249-14254, 1997

PubMed Abstract: Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.

PubMed: 9405598
DOI: 10.1073/pnas.94.26.14249

Experimental method

X-RAY DIFFRACTION (2.3 Å)