Comparative modeling of the three-dimensional structures of family 3 glycoside hydrolases

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Abstract
There are approximately 100 known members of the family 3 group of glycoside hydrolases, most of which are classified as β‐glucosidases and originate from microorganisms. The only family 3 glycoside hydrolase for which a three‐dimensional structure is available is a β‐glucan exohydrolase from barley. The structural coordinates of the barley enzyme is used here to model representatives from distinct phylogenetic clusters within the family. The majority of family 3 hydrolases have an NH2‐terminal (α/β)8 barrel connected by a short linker to a second domain, which adopts an (α/β)6 sandwich fold. In two bacterial β‐glucosidases, the order of the domains is reversed. The catalytic nucleophile, equivalent to D285 of the barley β‐glucan exohydrolase, is absolutely conserved across the family. It is located on domain 1, in a shallow site pocket near the interface of the domains. The likely catalytic acid in the barley enzyme, E491, is on domain 2. Although similarly positioned acidic residues are present in closely related members of the family, the equivalent amino acid in more distantly related members is either too far from the active site or absent. In the latter cases, the role of catalytic acid is probably assumed by other acidic amino acids from domain 1. Proteins 2000;41:257–269.