PDBsum entry: 1ayu

Hydrolase

PDB id: 1ayu

Contents

Protein chain

215 a.a. *

Ligands

INA

Waters ×66

* Residue conservation analysis

PDB id:

1ayu

Name:

Hydrolase

Title:

Crystal structure of cysteine protease human cathepsin k in complex with a covalent symmetric biscarbohydrazide inhibitor

Structure:

Cathepsin k. Chain: a. Engineered: yes. Other_details: inhibitor covalently bound to active site cys 25

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: sf21. Cell: osteoclast. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

2.20Å R-factor: 0.208 R-free: 0.318

Authors:

B.Zhao,W.W.Smith,C.A.Janson,S.S.Abdel-Meguid

Key ref:

S.K.Thompson et al. (1997). Design of potent and selective human cathepsin K inhibitors that span the active site. Proc Natl Acad Sci U S A, 94, 14249-14254. PubMed id: 9405598 DOI: 10.1073/pnas.94.26.14249

Date:

10-Nov-97 Release date: 25-Nov-98

Protein chain

P43235  (CATK_HUMAN) -  Cathepsin K

Seq: 329 a.a.

Struc: 215 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.22.38 - Cathepsin K.
• Reaction: Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg.

 Gene Ontology (GO) functional annotation 

• Biological process: proteolysis (1 term)
• Biochemical function: cysteine-type peptidase activity (2 terms)

DOI no: 10.1073/pnas.94.26.14249

Proc Natl Acad Sci U S A 94:14249-14254 (1997)

PubMed id: 9405598

Design of potent and selective human cathepsin K inhibitors that span the active site.

S.K.Thompson, S.M.Halbert, M.J.Bossard, T.A.Tomaszek, M.A.Levy, B.Zhao, W.W.Smith, S.S.Abdel-Meguid, C.A.Janson, K.J.D'Alessio, M.S.McQueney, B.Y.Amegadzie, C.R.Hanning, R.L.DesJarlais, J.Briand, S.K.Sarkar, M.J.Huddleston, C.F.Ijames, S.A.Carr, K.T.Garnes, A.Shu, J.R.Heys, J.Bradbeer, D.Zembryki, L.Lee-Rykaczewski, I.E.James, M.W.Lark, F.H.Drake, M.Gowen, J.G.Gleason, D.F.Veber.

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.

Selected figure(s)

Figure 1.
Fig. 1. The evolution of inhibitors 4-10.

Figure 3.
Fig. 3. (A) Inhibition of cathepsin K by 4 and 8. (B) Proposed general mechanism of proteolysis by cathepsin K.

Figures were selected by an automated process.