Xt. Zhu et al., Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors, STRUCT F D, 7(6), 1999, pp. 651-661
Background: The lymphocyte-specific kinase Lck is a member of the Src famil
y of non-receptor tyrosine kinases. Lck catalyzes the initial phosphorylati
on of T-cell receptor components that is necessary for signal transduction
and T-cell activation. On the basis of both biochemical and genetic studies
, Lck is considered an attractive cell-specific target for the design of no
vel T-cell immunosuppressants. To date, the lack of detailed structural inf
ormation on the mode of inhibitor binding to Lck has limited the discovery
of novel Lck inhibitors.
Results: We report here the high-resolution crystal structures of an activa
ted Lck kinase domain in complex with three structurally distinct ATP-compe
titive inhibitors: AMP-PNP (a non-selective, non-hydrolyzable ATP analog);
staurosporine (a potent but non-selective protein kinase inhibitor); and PP
2 (a potent Src family selective protein tyrosine kinase inhibitor). Compar
ison of these structures reveals subtle but important structural changes at
the ATP-binding site. Furthermore, PP2 is found to access a deep, hydropho
bic pocket near the ATP-binding cleft of the enzyme; this binding pocket is
not occupied by either AMP-PNP or staurosporine.
Conclusions: The potency of staurosporine against Lck derives in part from
an induced movement of the glycine-rich loop of the enzyme upon binding of
this ligand, which maximizes the van der Waals interactions present in the
complex. In contrast, PP2 binds tightly and selectively to Lck and other Sr
c family kinases by making additional contacts in a deep, hydrophobic pocke
t adjacent to the ATP-binding site; the amino acid composition of this pock
et is unique to Src family kinases. The structures of these Lck complexes o
ffer useful structural insights as they demonstrate that kinase selectivity
can be achieved with small-molecule inhibitors that exploit subtle topolog
ical differences among protein kinases.