PDBsum entry: 1bqi

Hydrolase

PDB-id: 1bqi

Contents

Description

Header details

Header records

References

PROCHECK

Protein chain

212 a.a. *

Ligands

SBA

Waters ×42

* Residue conservation analysis

Tools

Clefts Calculation

PDB id:

1bqi

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

UniProt:

P00784 (PAPA1_CARPA)

Seq:

Struc:

Seq:

345 a.a.

Struc:

212 a.a.*

Key:	PfamA domain
Secondary structure	CATH domain

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme class:

E.C.3.4.22.2   [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'.

Resolution:

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]

Date:

16-Aug-98

Release date:

16-Aug-99

Quick_links

Procheck

Clefts

Surface

Key reference

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.

ABSTRACT

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.