PDBsum entry: 1tu6

Hydrolase

PDB id: 1tu6

Contents

Protein chains

215 a.a. *

Ligands

SO4 ×3

FSP ×2

Waters ×371

* Residue conservation analysis

PDB id:

1tu6

Name:

Hydrolase

Title:

Cathepsin k complexed with a ketoamide inhibitor

Structure:

Cathepsin k. Chain: a, b. Fragment: cathepsin k: mature form (residues 115-329). Synonym: cathepsin o, cathepsin x, cathepsin o2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ctsk, ctso, ctso2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Biol. unit:

Dimer (from PQS)

Resolution:

1.75Å R-factor: 0.190 R-free: 0.214

Authors:

D.G.Barrett,J.G.Catalano,D.N.Deaton,A.M.Hassell,S.T.Long, A.B.Miller,L.R.Miller,L.M.Shewchuk,K.J.Wells-Knecht, L.L.Wright

Key ref:

D.G.Barrett et al. (2004). Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions. Bioorg Med Chem Lett, 14, 4897-4902. PubMed id: 15341947 DOI: 10.1016/j.bmcl.2004.07.031

Date:

24-Jun-04 Release date: 21-Sep-04

Protein chains

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: 10.1016/j.bmcl.2004.07.031

Bioorg Med Chem Lett 14:4897-4902 (2004)

PubMed id: 15341947

Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions.

D.G.Barrett, J.G.Catalano, D.N.Deaton, A.M.Hassell, S.T.Long, A.B.Miller, L.R.Miller, L.M.Shewchuk, K.J.Wells-Knecht, D.H.Willard, L.L.Wright.

ABSTRACT

A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.