1CPJ

CRYSTAL STRUCTURES OF RECOMBINANT RAT CATHEPSIN B AND A CATHEPSIN B-INHIBITOR COMPLEX: IMPLICATIONS FOR STRUCTURE-BASED INHIBITOR DESIGN

1CPJ の概要

• エントリーDOI: 10.2210/pdb1cpj/pdb
• 分子名称: CATHEPSIN B (2 entities in total)
• 機能のキーワード: thiol protease, hydrolase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Lysosome: P00787
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 56883.12

構造登録者

Huber, C.P.,Jia, Z. (登録日: 1995-07-17, 公開日: 1995-12-07, 最終更新日: 2024-10-23)

主引用文献

Jia, Z.,Hasnain, S.,Hirama, T.,Lee, X.,Mort, J.S.,To, R.,Huber, C.P.
Crystal structures of recombinant rat cathepsin B and a cathepsin B-inhibitor complex. Implications for structure-based inhibitor design.
J.Biol.Chem., 270:5527-5533, 1995

PubMed Abstract: The lysosomal cysteine proteinase cathepsin B (EC 3.4.22.1) plays an important role in protein catabolism and has also been implicated in various disease states. The crystal structures of two forms of native recombinant rat cathepsin B have been determined. The overall folding of rat cathepsin B was shown to be very similar to that of the human liver enzyme. The structure of the native enzyme containing an underivatized active site cysteine (Cys29) showed the active enzyme conformation to be similar to that determined previously for the oxidized form. In a second structure Cys29 was derivatized with the reversible blocking reagent pyridyl disulfide. In this structure large side chain conformational changes were observed for the two key catalytic residues Cys29 and His199, demonstrating the potential flexibility of these side chains. In addition the structure of the complex between rat cathepsin B and the inhibitor benzyloxycarbonyl-Arg-Ser(O-Bzl) chloromethylketone was determined. The complex structure showed that very little conformational change occurs in the enzyme upon inhibitor binding. It also allowed visualization of the interaction between the enzyme and inhibitor. In particular the interaction between Glu245 and the P2 Arg residue was clearly demonstrated, and it was found that the benzyl group of the P1 substrate residue occupies a large hydrophobic pocket thought to represent the S'1 subsite. This may have important implications for structure-based design of cathepsin B inhibitors.

PubMed: 7890671
DOI: 10.1074/jbc.270.10.5527

実験手法

X-RAY DIFFRACTION (2.2 Å)