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 A resolution crystal structure of the two-domain protein ssKex2 in complex with an Ac-Ala-Lys-boroArg inhibitor (R = 20.9%, R(free) = 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 beta strands and may potentially be involved, along with the buried Ca(2+) ion, in creating the highly determined binding site for P(1) arginine.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Binding Sites
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Boronic Acids / chemistry*
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Boronic Acids / metabolism
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Boronic Acids / pharmacology
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Calcium / chemistry
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Calcium / metabolism
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Crystallography, X-Ray
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Models, Molecular
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Oligopeptides / chemistry*
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Oligopeptides / metabolism
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Oligopeptides / pharmacology
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Proprotein Convertases*
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Protease Inhibitors / chemistry*
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Protease Inhibitors / metabolism
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Protease Inhibitors / pharmacology
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Saccharomyces cerevisiae Proteins*
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Static Electricity
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Substrate Specificity
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Subtilisins / antagonists & inhibitors
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Subtilisins / chemistry*
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Subtilisins / metabolism
Substances
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Amino Acids
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Boronic Acids
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Oligopeptides
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Protease Inhibitors
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Saccharomyces cerevisiae Proteins
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Proprotein Convertases
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Subtilisins
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KEX2 protein, S cerevisiae
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Calcium