PDBsum entry: 1nl6

Hydrolase

PDB id: 1nl6

Contents

Protein chains

215 a.a. *

Ligands

750 ×2

* Residue conservation analysis

PDB id:

1nl6

Name:

Hydrolase

Title:

Crystal structure of the cysteine protease human cathepsin k in complex with a covalent azepanone inhibitor

Structure:

Cathepsin k. Chain: a, b. Synonym: cathepsin o, cathepsin x, cathepsin o2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.80Å R-factor: 0.246 R-free: 0.298

Authors:

W.W.Smith,C.A.Janson,B.Zhao

Key ref:

R.W.Marquis et al. (2001). Azepanone-based inhibitors of human and rat cathepsin K. J Med Chem, 44, 1380-1395. PubMed id: 11311061 DOI: 10.1021/jm000481x

Date:

06-Jan-03 Release date: 14-Jan-03

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: 10.1021/jm000481x

J Med Chem 44:1380-1395 (2001)

PubMed id: 11311061

Azepanone-based inhibitors of human and rat cathepsin K.

R.W.Marquis, Y.Ru, S.M.LoCastro, J.Zeng, D.S.Yamashita, H.J.Oh, K.F.Erhard, L.D.Davis, T.A.Tomaszek, D.Tew, K.Salyers, J.Proksch, K.Ward, B.Smith, M.Levy, M.D.Cummings, R.C.Haltiwanger, G.Trescher, B.Wang, M.E.Hemling, C.J.Quinn, H.Y.Cheng, F.Lin, W.W.Smith, C.A.Janson, B.Zhao, M.S.McQueney, K.D'Alessio, C.P.Lee, A.Marzulli, R.A.Dodds, S.Blake, S.M.Hwang, I.E.James, C.J.Gress, B.R.Bradley, M.W.Lark, M.Gowen, D.F.Veber.

ABSTRACT

The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.