PDBsum entry 1bp4

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Hydrolase PDB id
Protein chain
212 a.a.
Waters ×88

References listed in PDB file
Key reference
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.
Authors 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.
Ref. J Med Chem, 1998, 41, 4567-4576. [DOI no: 10.1021/jm980249f]
PubMed id 9804696
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.
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