The active site substrate specificities of v-Abl and c-Src are compare
d and contrasted, Both enzymes catalyze the phosphorylation of a broad
assortment of peptide-bound aliphatic and aromatic alcohols, such as
achiral and simple straight chain residues, In addition, both protein
kinases exhibit a ''dual specificity'' with respect to the ability to
utilize D- and L-configurational isomers as substrates, However, c-Src
and v-Abl are extremely inefficient as catalysts for certain structur
al arrangements, including secondary alcohols and primary alcohols con
taining large substituents in close proximity to the hydroxyl moiety.
In addition to these similarities, these enzymes also display notewort
hy differences in catalytic behavior, Whereas c-Src exhibits a modest
preference for aromatic versus aliphatic alcohols, v-Abl does not, Mos
t dramatic is the ability of c-Src to utilize short chain alcohols as
substrates, an activity virtually absent from the catalytic repertoire
of v-Abl, The implications of these observations are 2-fold. First, b
ecause both enzymes are able to accommodate a wide variety of structur
al variants within their respective active site regions, there exists
a substantial degree of flexibility with respect to inhibitor design,
Second, because these enzymes exhibit disparate active site specificit
ies, it is possible that other tyrosine-specific protein kinases will
display unique substrate specificities as well, Consequently, it may u
ltimately be possible to exploit these differences to generate inhibit
ors that precisely target specific protein kinases.