PDBsum entry 1bqi

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Hydrolase PDB id
Jmol PyMol
Protein chain
212 a.a. *
Waters ×42
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Use of papain as a model for the structure-based design of cathepsin k inhibitors. Crystal structures of two papain inhibitor complexes demonstrate binding to s'-subsites.
Structure: Papain. Chain: a. Other_details: methoxymethylketone bound non-covalently in s'-subsite
Source: Carica papaya. Papaya. Organism_taxid: 3649
2.50Å     R-factor:   0.217     R-free:   0.306
Authors: J.M.Lalonde,B.Zhao,W.W.Smith,C.A.Janson,R.L.Desjarlais, T.A.Tomaszek,T.J.Carr,S.K.Thompson,D.S.Yamashita,D.F.Veber, S.S.Abdel-Mequid
Key ref: J.M.LaLonde et al. (1998). Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites. J Med Chem, 41, 4567-4576. PubMed id: 9804696 DOI: 10.1021/jm980249f
16-Aug-98     Release date:   16-Aug-99    
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Protein chain
Pfam   ArchSchema ?
P00784  (PAPA1_CARPA) -  Papain
345 a.a.
212 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Papain.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of proteins with broad specificity for peptide bonds, with preference for a residue bearing a large hydrophobic sidechain at the P2 position. Does not accept Val at P1'.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     cysteine-type peptidase activity     1 term  


DOI no: 10.1021/jm980249f J Med Chem 41:4567-4576 (1998)
PubMed id: 9804696  
Use of papain as a model for the structure-based design of cathepsin K inhibitors: crystal structures of two papain-inhibitor complexes demonstrate binding to S'-subsites.
J.M.LaLonde, B.Zhao, W.W.Smith, C.A.Janson, R.L.DesJarlais, T.A.Tomaszek, T.J.Carr, S.K.Thompson, H.J.Oh, D.S.Yamashita, D.F.Veber, S.S.Abdel-Meguid.
Papain has been used as a surrogate enzyme in a drug design effort to obtain potent and selective inhibitors of cathepsin K, a new member of the papain superfamily of cysteine proteases that is selectively and highly expressed in osteoclasts and is implicated in bone resorption. Here we report the crystal structures of two papain-inhibitor complexes and the rational design of novel cathepsin K inhibitors. Unlike previously known crystal structures of papain-inhibitor complexes, our papain structures show ligand binding extending deep within the S'-subsites. The two inhibitor complexes, carbobenzyloxyleucinyl-leucinyl-leucinal and carbobenzyloxy-L-leucinyl-L-leucinyl methoxymethyl ketone, were refined to 2.2- and 2.5-A resolution with R-factors of 0.190 and 0. 217, respectively. The S'-subsite interactions with the inhibitors are dominated by an aromatic-aromatic stacking and an oxygen-aromatic ring edge interaction. The knowledge of S'-subsite interactions led to a design strategy for an inhibitor spanning both subsites and yielded a novel, symmetric inhibitor selective for cathepsin K. Simultaneous exploitation of both S- and S'-sites provides a general strategy for the design of cysteine protease inhibitors having high specificity to their target enzymes.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21181719 M.Shokhen, N.Khazanov, and A.Albeck (2011).
The mechanism of papain inhibition by peptidyl aldehydes.
  Proteins, 79, 975-985.  
19064273 K.Volcy, and S.Dewhurst (2009).
Proteasome inhibitors enhance bacteriophage lambda (lambda) mediated gene transfer in mammalian cells.
  Virology, 384, 77-87.  
19430116 T.K.Nandi, H.R.Bairagya, B.P.Mukhopadhyay, K.Sekar, D.Sukul, and A.K.Bera (2009).
Conserved water-mediated H-bonding dynamics of catalytic Asn 175 in plant thiol protease.
  J Biosci, 34, 27-34.  
18598021 M.P.Beavers, M.C.Myers, P.P.Shah, J.E.Purvis, S.L.Diamond, B.S.Cooperman, D.M.Huryn, and A.B.Smith (2008).
Molecular docking of cathepsin L inhibitors in the binding site of papain.
  J Chem Inf Model, 48, 1464-1472.  
18403718 P.P.Shah, M.C.Myers, M.P.Beavers, J.E.Purvis, H.Jing, H.J.Grieser, E.R.Sharlow, A.D.Napper, D.M.Huryn, B.S.Cooperman, A.B.Smith, and S.L.Diamond (2008).
Kinetic characterization and molecular docking of a novel, potent, and selective slow-binding inhibitor of human cathepsin L.
  Mol Pharmacol, 74, 34-41.  
18253767 S.S.Gunatilleke, Oliveira, J.A.McCammon, and A.M.Barrios (2008).
Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study.
  J Biol Inorg Chem, 13, 555-561.  
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.  
  11257231 Y.Huang, Y.C.Park, R.L.Rich, D.Segal, D.G.Myszka, and H.Wu (2001).
Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.
  Cell, 104, 781-790.
PDB code: 1i4o
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