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PDBsum entry 1the
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Hydrolase/hydrolase inhibitor
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PDB id
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1the
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of recombinant rat cathepsin b and a cathepsin b-Inhibitor complex. Implications for structure-Based inhibitor design.
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Authors
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Z.Jia,
S.Hasnain,
T.Hirama,
X.Lee,
J.S.Mort,
R.To,
C.P.Huber.
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Ref.
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J Biol Chem, 1995,
270,
5527-5533.
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PubMed id
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Abstract
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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.
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Secondary reference #1
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Title
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Crystallization of recombinant rat cathepsin b.
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Authors
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X.Lee,
F.R.Ahmed,
T.Hirama,
C.P.Huber,
D.R.Rose,
R.To,
S.Hasnain,
A.Tam,
J.S.Mort.
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Ref.
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J Biol Chem, 1990,
265,
5950-5951.
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PubMed id
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