PDBsum entry 2f7d

Hydrolase

PDB id: 2f7d

Contents

Protein chain

215 a.a. *

Ligands

NOQ

Waters ×97

* Residue conservation analysis

PDB id:

2f7d

Name:

Hydrolase

Title:

A mutant rabbit cathepsin k with a nitrile inhibitor

Structure:

Cathepsin k. Chain: a. Synonym: oc-2 protein. Engineered: yes. Mutation: yes

Source:

Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Gene: ctsk. Expressed in: pichia pastoris. Expression_system_taxid: 4922

Resolution:

1.90Å R-factor: 0.174 R-free: 0.205

Authors:

J.R.Somoza

Key ref:

S.N.Crane et al. (2006). Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K. J Med Chem, 49, 1066-1079. PubMed id: 16451072

Date:

30-Nov-05 Release date: 07-Mar-06

Protein chain

P43236  (CATK_RABIT) -  Cathepsin K from Oryctolagus cuniculus

Seq: 329 a.a.

Struc: 215 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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.

J Med Chem 49:1066-1079 (2006)

PubMed id: 16451072

Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.

S.N.Crane, W.C.Black, J.T.Palmer, D.E.Davis, E.Setti, J.Robichaud, J.Paquet, R.M.Oballa, C.I.Bayly, D.J.McKay, J.R.Somoza, N.Chauret, C.Seto, J.Scheigetz, G.Wesolowski, F.Massé, S.Desmarais, M.Ouellet.

ABSTRACT

A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.