Mechanisms of PI3Kβ-selective inhibition revealed by reciprocal mutagenesis.
The p110β isoform of PI3 kinase (PI3Kβ) has been implicated in pathological disorders such as thrombosis and cancer and a number of PI3Kβ-selective inhibitors have recently progressed into clinical studies. Although crystallography studies identify a binding site conformation favored by the inhibitors, no specific interaction explains the observed selectivity. Using site-directed mutagenesis we have identified a specific tyrosine residue of the binding site Y778 that dictates the ability of the PI3Kβ isoform to bind these inhibitors. When mutated to isoleucine, PI3Kβ has reduced ability to present a specific cryptic binding site into which a range of reported PI3Kβ inhibitors can bind, and conversely when tyrosine is introduced into the same position in PI3Kα, the same inhibitors gain potency. The results provide a cogent explanation for the selectivity profiles displayed by these PI3K inhibitors and maybe others as well.
Zhaohua
Z
Zheng
Michelle S
MS
Miller
Ian G
IG
Jennings
Philip E
PE
Thompson
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D016296:Mutagenesis; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors