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Hydrolase PDB-id
1cpj
Biological unit* = asymmetric unit, as shown
(*as deduced by PQS)
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Protein chains
253 a.a. *
Waters ×190

* Residue conservation analysis
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PDB id: 1cpj
Name: Hydrolase
Title: Crystal structures of recombinant rat cathepsin b and a cathepsin b-inhibitor complex: implications for structure- based inhibitor design

Structure:
Cathepsin b. Chain: a, b. Engineered: yes. Mutation: yes

Source:
Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: cdna. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932.

Biological unit:
Dimer (from PQS)

UniProt:
Chains A, B: P00787 (CATB_RAT)
Pfam   ArchSchema ?
Seq:
Struc:
Seq: 339 a.a.
Struc: 253 a.a.*
Key:    PfamA domain
 Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme class:
E.C.3.4.22.1   [IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

Reaction:
Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg-|-Xaa bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides.

Resolution:
2.20Å

R-factor:
0.175

Authors:
C.P.Huber,Z.Jia

Key ref:
Z.Jia et al. (1995). Crystal structures of recombinant rat cathepsin B and a cathepsin B-inhibitor complex. Implications for structure-based inhibitor design.. J Biol Chem, 270, 5527-5533. [PubMed id: 7890671] [DOI: 10.1074/jbc.270.10.5527]

Date:
17-Jul-95

Release date:
07-Dec-95
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    Key reference    
 
 
DOI no: 10.1074/jbc.270.10.5527 J Biol Chem 270:5527-5533 (1995)
PubMed id: 7890671  
 
 
Crystal structures of recombinant rat cathepsin B and a cathepsin B-inhibitor complex. Implications for structure-based inhibitor design.
Z.Jia, S.Hasnain, T.Hirama, X.Lee, J.S.Mort, R.To, C.P.Huber.
 
  ABSTRACT  
 
The lysosomal cysteine proteinase cathepsin B (EC 3.4.22.1) plays an important role in protein catabolism and has also been implicated in various disease states. The crystal structures of two forms of native recombinant rat cathepsin B have been determined. The overall folding of rat cathepsin B was shown to be very similar to that of the human liver enzyme. The structure of the native enzyme containing an underivatized active site cysteine (Cys29) showed the active enzyme conformation to be similar to that determined previously for the oxidized form. In a second structure Cys29 was derivatized with the reversible blocking reagent pyridyl disulfide. In this structure large side chain conformational changes were observed for the two key catalytic residues Cys29 and His199, demonstrating the potential flexibility of these side chains. In addition the structure of the complex between rat cathepsin B and the inhibitor benzyloxycarbonyl-Arg-Ser(O-Bzl) chloromethylketone was determined. The complex structure showed that very little conformational change occurs in the enzyme upon inhibitor binding. It also allowed visualization of the interaction between the enzyme and inhibitor. In particular the interaction between Glu245 and the P2 Arg residue was clearly demonstrated, and it was found that the benzyl group of the P1 substrate residue occupies a large hydrophobic pocket thought to represent the S'1 subsite. This may have important implications for structure-based design of cathepsin B inhibitors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19225106 Q.Yao, J.Cui, Y.Zhu, G.Wang, L.Hu, C.Long, R.Cao, X.Liu, N.Huang, S.Chen, L.Liu, and F.Shao (2009).
A bacterial type III effector family uses the papain-like hydrolytic activity to arrest the host cell cycle.
  Proc Natl Acad Sci U S A, 106, 3716-3721.
PDB codes: 3eir 3eit
17617796 E.Wieczerzak, S.Rodziewicz-Motowidło, E.Jankowska, A.Giełdoń, and J.Ciarkowski (2007).
An enormously active and selective azapeptide inhibitor of cathepsin B.
  J Pept Sci, 13, 536-543.  
14694194 M.Zhu, F.Shao, R.W.Innes, J.E.Dixon, and Z.Xu (2004).
The crystal structure of Pseudomonas avirulence protein AvrPphB: a papain-like fold with a distinct substrate-binding site.
  Proc Natl Acad Sci U S A, 101, 302-307.
PDB code: 1ukf
12554931 D.Turk, and G.Guncar (2003).
Lysosomal cysteine proteases (cathepsins): promising drug targets.
  Acta Crystallogr D Biol Crystallogr, 59, 203-213.  
12833545 M.Sulpizi, A.Laio, J.VandeVondele, A.Cattaneo, U.Rothlisberger, and P.Carloni (2003).
Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations.
  Proteins, 52, 212-224.  
12668429 M.Sulpizi, U.Rothlisberger, and P.Carloni (2003).
Molecular dynamics studies of caspase-3.
  Biophys J, 84, 2207-2215.  
12454480 R.Reutzel, S.K.Boehlein, L.Govindasamy, R.B.Brenes, M.Agbandje-McKenna, S.M.Schuster, and R.McKenna (2002).
Crystallization and preliminary X-ray analysis of the tumor metastasis factor p37.
  Acta Crystallogr D Biol Crystallogr, 58, 2141-2144.  
11598875 D.Peters, and J.Peters (2001).
The pseudomolecule method and the structure of globular proteins. II. The example of ribonuclease F1 and T1.
  Biopolymers, 59, 402-410.  
9914503 C.Serveau, G.Lalmanach, I.Hirata, J.Scharfstein, M.A.Juliano, and F.Gauthier (1999).
Discrimination of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, and mammalian cathepsins B and L, by a pH-inducible fluorogenic substrate of trypanosomal cysteine proteinases.
  Eur J Biochem, 259, 275-280.  
10089358 O.Carugo, and P.Argos (1999).
Reliability of atomic displacement parameters in protein crystal structures.
  Acta Crystallogr D Biol Crystallogr, 55, 473-478.  
  9568890 A.R.Khan, and M.N.James (1998).
Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes.
  Protein Sci, 7, 815-836.  
  9655332 M.E.McGrath, J.T.Palmer, D.Brömme, and J.R.Somoza (1998).
Crystal structure of human cathepsin S.
  Protein Sci, 7, 1294-1302.  
9015749 D.A.Giegel (1997).
ICE processing and kinetic mechanism.
  J Cell Biochem, 64, 11-18.  
9362483 R.Tikkanen, M.Peltola, C.Oinonen, J.Rouvinen, and L.Peltonen (1997).
Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase.
  EMBO J, 16, 6684-6693.  
  9260273 S.A.Gillmor, C.S.Craik, and R.J.Fletterick (1997).
Structural determinants of specificity in the cysteine protease cruzain.
  Protein Sci, 6, 1603-1611.
PDB codes: 1aim 2aim
8973203 D.Maes, J.Bouckaert, F.Poortmans, L.Wyns, and Y.Looze (1996).
Structure of chymopapain at 1.7 A resolution.
  Biochemistry, 35, 16292-16298.
PDB code: 1yal
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. Where a reference describes a PDB structure, the PDB codes are shown on the right.