2.4 Å resolution crystal structure of the prototypical hormone-processing protease Kex2 in complex with an Ala-Lys-Arg boronic acid inhibitor

Todd Holyoak, Mark A. Wilson, Timothy D. Fenn, Charles A. Kettner, Gregory A. Petsko, Robert S. Fuller, Dagmar Ringe

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Abstract

This paper reports the first structure of a member of the Kex2/furin family of eukaryotic pro-protein processing proteases, which cleave sites consisting of pairs or clusters of basic residues. Reported is the 2.4 Å resolution crystal structure of the two-domain protein ssKex2 in complex with an Ac-Ala- Lys-boroArg inhibitor (R = 20.9%, Rfree = 24.5%). The Kex2 proteolytic domain is similar in its global fold to the subtilisin-like superfamily of degradative proteases. Analysis of the complex provides a structural basis for the extreme selectivity of this enzyme family that has evolved from a nonspecific subtilisin-like ancestor. The P-domain of ssKex2 has a novel jelly roll like fold consisting of nine β strands and may potentially be involved, along with the buried Ca2+ ion, in creating the highly determined binding site for P1 arginine.

Original languageEnglish (US)
Pages (from-to)6709-6718
Number of pages10
JournalBiochemistry
Volume42
Issue number22
DOIs
StatePublished - Jun 10 2003

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ASJC Scopus subject areas

  • Biochemistry

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