Loading…

X-Ray crystal structure of papain complexed with cathepsin B-specific covalent-type inhibitor: substrate specificity and inhibitory activity

The Ile–Pro sequence of CA074, potent covalent-type inhibitor, is necessary to exhibit the specificity for cathepsin B, but not for papain. In order to elucidate how its sequence binds to papain and why such binding does not exhibit the specificity for papain at the atomic level, two CA074-related c...

Full description

Saved in:
Bibliographic Details
Published in:Biochimica et biophysica acta 1998-03, Vol.1383 (1), p.93-100
Main Authors: Matsumoto, Keita, Murata, Mitsuo, Sumiya, Shigeyuki, Mizoue, Kazutoshi, Kitamura, Kunihiro, Ishida, Toshimasa
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The Ile–Pro sequence of CA074, potent covalent-type inhibitor, is necessary to exhibit the specificity for cathepsin B, but not for papain. In order to elucidate how its sequence binds to papain and why such binding does not exhibit the specificity for papain at the atomic level, two CA074-related compounds, 1 ( N-( l-3-carboxyloxirane-2-carbonyl)- l-isoleucyl- l-proline) and 2 ( N-( l-3-carboxyloxirane-2-carbonyl)- l-isoleucyl-diethylamide), were designed and their structure—inhibitory activity relationship was investigated by the X-ray crystal analyses of the complexes with papain. The Ile–Pro moiety of 1 was located at the S 2 and S 3 subsites consisting of Val-133, Val-157, and Asp-158 and of Tyr-61, Gly-66, and Tyr-67 residues of papain, respectively, which is in contrast with the binding of CA074 to S n ′ ( n=1∼2) subsites in the complex with cathepsin B. Although 2 in the complex with papain showed the similar binding pattern to 1, its inhibitory activity was about two-fold higher than of 1, suggesting the importance of tight S 3–P 3 hydrophobic interaction for the activity. The difference of the substrate specificity between papain and cathepsin B has also been discussed based on the X-ray results of the present and cathepsin B-inhibitor complexes.
ISSN:0167-4838
0006-3002
1879-2588
DOI:10.1016/S0167-4838(97)00187-8