1BQI

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.

1BQI の概要

• エントリーDOI: 10.2210/pdb1bqi/pdb
• 分子名称: PAPAIN, CARBOBENZYLOXY-(L)-LEUCINYL-(L)LEUCINYL METHOXYMETHYLKETONE (3 entities in total)
• 機能のキーワード: hydrolase, sulfhydryl proteinase, papain
• 由来する生物種: Carica papaya (papaya)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23857.88

構造登録者

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. (登録日: 1998-08-16, 公開日: 1999-08-16, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)