cb400663k_si_001.pdf (4.18 MB)
Conformation-Selective Inhibitors Reveal Differences in the Activation and Phosphate-Binding Loops of the Tyrosine Kinases Abl and Src
journal contribution
posted on 2013-12-20, 00:00 authored by Sanjay
B. Hari, B. Gayani K. Perera, Pratistha Ranjitkar, Markus A. Seeliger, Dustin J. MalyOver the past decade, an increasingly
diverse array of potent and
selective inhibitors that target the ATP-binding sites of protein
kinases have been developed. Many of these inhibitors, like the clinically
approved drug imatinib (Gleevec), stabilize a specific catalytically
inactive ATP-binding site conformation of their kinases targets. Imatinib
is notable in that it is highly selective for its kinase target, Abl,
over other closely related tyrosine kinases, such as Src. In addition,
imatinib is highly sensitive to the phosphorylation state of Abl’s
activation loop, which is believed to be a general characteristic
of all inhibitors that stabilize a similar inactive ATP-binding site
conformation. In this report, we perform a systematic analysis of
a diverse series of ATP-competitive inhibitors that stabilize a similar
inactive ATP-binding site conformation as imatinib with the tyrosine
kinases Src and Abl. In contrast to imatinib, many of these inhibitors
have very similar potencies against Src and Abl. Furthermore, only
a subset of this class of inhibitors is sensitive to the phosphorylation
state of the activation loop of these kinases. In attempting to explain
this observation, we have uncovered an unexpected correlation between
Abl’s activation loop and another flexible active site feature,
called the phosphate-binding loop (p-loop). These studies shed light
on how imatinib is able to obtain its high target selectivity and
reveal how the conformational preference of flexible active site regions
can vary between closely related kinases.