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Hydrolase PDB id
1vsn
Jmol
Contents
Protein chain
215 a.a. *
Ligands
NFT
Waters ×269
* Residue conservation analysis
PDB id:
1vsn
Name: Hydrolase
Title: Crystal structure of a potent small molecule inhibitor bound to cathepsin k
Structure: Cathepsin k. Chain: a. Fragment: cathepsin k. Synonym: cathepsin o, cathepsin x, cathepsin o2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ctsk, ctso, ctso2. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Resolution:
2.00Å     R-factor:   0.171     R-free:   0.209
Authors: M.Mcgrath
Key ref: C.S.Li et al. (2006). Identification of a potent and selective non-basic cathepsin K inhibitor. Bioorg Med Chem Lett, 16, 1985-1989. PubMed id: 16413777 DOI: 10.1016/j.bmcl.2005.12.071
Date:
19-Mar-07     Release date:   24-Apr-07    
Supersedes: 2fdz
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P43235  (CATK_HUMAN) -  Cathepsin K
Seq:
Struc: 		329 a.a.
215 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 15 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.22.38  - Cathepsin K.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      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 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     cysteine-type peptidase activity     2 terms  

 

 
DOI no: 10.1016/j.bmcl.2005.12.071 Bioorg Med Chem Lett 16:1985-1989 (2006)
PubMed id: 16413777  
 
 
Identification of a potent and selective non-basic cathepsin K inhibitor.
C.S.Li, D.Deschenes, S.Desmarais, J.P.Falgueyret, J.Y.Gauthier, D.B.Kimmel, S.Léger, F.Massé, M.E.McGrath, D.J.McKay, M.D.Percival, D.Riendeau, S.B.Rodan, M.Thérien, V.L.Truong, G.Wesolowski, R.Zamboni, W.C.Black.
 
  ABSTRACT  
 
Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19082013 F.Petronijevic, C.Timmons, A.Cuzzupe, and P.Wipf (2009).
A microwave assisted intramolecular-furan-Diels-Alder approach to 4-substituted indoles.
  Chem Commun (Camb), 0, 104-106.  
  20126511 I.Podgorski (2009).
Future of anticathepsin K drugs: dual therapy for skeletal disease and atherosclerosis?
  Future Med Chem, 1, 21-34.  
  19700761 I.Podgorski, B.E.Linebaugh, J.E.Koblinski, D.L.Rudy, M.K.Herroon, M.B.Olive, and B.F.Sloane (2009).
Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis.
  Am J Pathol, 175, 1255-1269.  
19462037 M.Molteni, M.C.Bellucci, S.Bigotti, S.Mazzini, A.Volonterio, and M.Zanda (2009).
Psi[CH(CF(3))NH]Gly-peptides: synthesis and conformation analysis.
  Org Biomol Chem, 7, 2286-2296.  
19462390 N.Elders, E.Ruijter, F.J.de Kanter, E.Janssen, M.Lutz, A.L.Spek, and R.V.Orru (2009).
A multicomponent reaction towards N-(cyanomethyl)amides.
  Chemistry, 15, 6096-6099.  
  20725595 P.Wipf, J.Xiao, and C.R.Stephenson (2009).
Peptide-Like Molecules (PLMs): A Journey from Peptide Bond Isosteres to Gramicidin S Mimetics and Mitochondrial Targeting Agents.
  Chimia (Aarau), 63, 764-775.  
19453281 S.Desmarais, F.Massé, and M.D.Percival (2009).
Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools.
  Biol Chem, 390, 941-948.  
18073778 S.A.Stoch, and J.A.Wagner (2008).
Cathepsin K inhibitors: a novel target for osteoporosis therapy.
  Clin Pharmacol Ther, 83, 172-176.  
  18511517 V.M.Dejica, J.S.Mort, S.Laverty, M.D.Percival, J.Antoniou, D.J.Zukor, and A.R.Poole (2008).
Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage.
  Am J Pathol, 173, 161-169.  
17823898 M.Sani, A.Volonterio, and M.Zanda (2007).
The Trifluoroethylamine Function as Peptide Bond Replacement.
  ChemMedChem, 2, 1693-1700.  
16921579 W.C.Black, and M.D.Percival (2006).
The consequences of lysosomotropism on the design of selective cathepsin K inhibitors.
  Chembiochem, 7, 1525-1535.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.