CRYSTAL-STRUCTURES OF HINT DEMONSTRATE THAT HISTIDINE TRIAD PROTEINS ARE GALT-RELATED NUCLEOTIDE-BINDING PROTEINS

Histidine triad nucleotide-binding protein (HINT), a dimeric purine nu cleotide-binding protein from rabbit heart, is a member of the HIT (hi stidine triad) superfamily which includes HINT homologues and FHIT (HI T protein encoded at the chromosome 3 fragile site) homologues. Crysta l structures of HINT-nucleotide complexes demonstrate that the most co nserved residues in the superfamily mediate nucleotide binding and tha t the HIT motif forms part of the phosphate binding loop. Galactose-1- phosphate uridylyltransferase, whose deficiency causes galactosemia, c ontains tandem HINT domains with the same fold and mode of nucleotide binding as HINT despite having no overall sequence similarity, Feature s of FHIT, a diadenosine polyphosphate hydrolase and candidate tumour suppressor, are predicted from HINT-nucleotide structures.