Chymotryptic specificity determinants in the 1.0 A structure of the zinc-inhibited human tissue kallikrein 7

Debela, M., Hess, P., Magdolen, V., Schechter, N. M., Steiner, T., Huber, Robert, Bode, W. and Goettig, P. 2007. Chymotryptic specificity determinants in the 1.0 A structure of the zinc-inhibited human tissue kallikrein 7. Proceedings of the National Academy of Sciences of the United States of America 104 (41) , pp. 16086-16091. 10.1073/pnas.0707811104

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Abstract

hK7 or human stratum corneum chymotryptic enzyme belongs to the human tissue kallikrein (hKs) serine proteinase family and is strongly expressed in the upper layers of the epidermis. It participates in skin desquamation but is also implicated in diverse skin diseases and is a potential biomarker of ovarian cancer. We have solved x-ray structures of recombinant active hK7 at medium and atomic resolution in the presence of the inhibitors succinyl-Ala-Ala-Pro-Phe-chloromethyl ketone and Ala-Ala-Phe-chloromethyl ketone. The most distinguishing features of hK7 are the short 70–80 loop and the unique S1 pocket, which prefers P1 Tyr residues, as shown by kinetic data. Similar to several other kallikreins, the enzyme activity is inhibited by Zn2+ and Cu2+ at low micromolar concentrations. Biochemical analyses of the mutants H99A and H41F confirm that only the metal-binding site at His99 close to the catalytic triad accounts for the noncompetitive Zn2+ inhibition type. Additionally, hK7 exhibits large positively charged surface patches, representing putative exosites for prime side substrate recognition.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Last Modified:	24 Jun 2017 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/69984

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