The Stereochemistry of Substrate Binding to Chymotrypsin A

Abstract

The determination of the crystal structures of chymotrypsin Aα (Matthews et al., 1967; Sigler et al., 1968; Birktoft et al., 1969) and Aγ (Cohen et al., 1969; Davies et al., unpublished) have made possible the investigation of the stereochemical basis of substrate and inhibitor binding to this serine protease. The work of Blow and his colleagues (Steitz et al., 1969) with Aα established the nature of the pocket which provides the aromatic specificity of chymotrypsin. In this paper, through an examination of a series of oligopeptide chloromethyl ketone inhibitors, we extend this work to describe the mode of binding of the two residues adjacent to the N terminus of the scissile residue. In addition we describe some kinetic experiments with solutions of chymotrypsin which strongly support this model.