1BP4

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.

Summary for 1BP4

• Entry DOI: 10.2210/pdb1bp4/pdb
• Related PRD ID: PRD_001210
• Descriptor: PAPAIN, N-[(benzyloxy)carbonyl]-L-leucyl-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]-L-leucinamide (3 entities in total)
• Functional Keywords: hydrolase, sulfhydryl proteinase
• Biological source: Carica papaya (papaya)
• Total number of polymer chains: 1
• Total formula weight: 23926.98

Authors

Lalonde, J.M.,Zhao, B.,Smith, W.W.,Janson, C.A.,Desjarlais, R.L.,Tomaszek, T.A.,Carr, T.J.,Thompson, S.K.,Yamashita, D.S.,Veber, D.F.,Abdel-Mequid, S.S. (deposition date: 1998-08-12, release date: 1999-08-12, Last modification date: 2024-10-23)

Primary citation

LaLonde, J.M.,Zhao, B.,Smith, W.W.,Janson, C.A.,DesJarlais, R.L.,Tomaszek, T.A.,Carr, T.J.,Thompson, S.K.,Oh, H.J.,Yamashita, D.S.,Veber, D.F.,Abdel-Meguid, S.S.
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, 1998

PubMed 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.

PubMed: 9804696
DOI: 10.1021/jm980249f

Experimental method

X-RAY DIFFRACTION (2.2 Å)