STRUCTURAL FEATURES THAT SPECIFY TYROSINE KINASE-ACTIVITY DEDUCED FROM HOMOLOGY MODELING OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR

To identify structural features that distinguish protein-tyrosine kina ses from protein-serine kinases, a molecular model of the kinase domai n of epidermal growth factor receptor was constructed by substituting its amino acid sequence for the amino acid sequence of the catalytic s ubunit of cAMP-dependent protein kinase in a 2.7-angstrom refined crys tallographic model. General folding was conserved as was the configura tion of invariant residues at the active site. Two sequence motifs tha t distinguish the two families correspond to loops that converge at th e active site of the enzyme. A conserved arginine in the catalytic loo p is proposed to interact with the gamma phosphate of ATP. The second loop provides a binding surface that positions the tyrosine of the sub strate. A positively charged surface provides additional sites for sub strate recognition.