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A Novel Mechanism by Which Small Molecule Inhibitors Induce the DFG Flip in Aurora A
journal contribution
posted on 2012-04-20, 00:00 authored by Mathew
P. Martin, Jin-Yi Zhu, Harshani R. Lawrence, Roberta Pireddu, Yunting Luo, Riazul Alam, Sevil Ozcan, Said M. Sebti, Nicholas J. Lawrence, Ernst SchönbrunnMost protein kinases share a DFG (Asp-Phe-Gly) motif
in the ATP
site that can assume two distinct conformations, the active DFG-in
and the inactive DFG-out states. Small molecule inhibitors able to
induce the DFG-out state have received considerable attention in kinase
drug discovery. Using a typical DFG-in inhibitor scaffold of Aurora
A, a kinase involved in the regulation of cell division, we found
that halogen and nitrile substituents directed at the N-terminally
flanking residue Ala273 induced global conformational changes in the
enzyme, leading to DFG-out inhibitors that are among the most potent
Aurora A inhibitors reported to date. The data suggest an unprecedented
mechanism of action, in which induced-dipole forces along the Ala273
side chain alter the charge distribution of the DFG backbone, allowing
the DFG to unwind. As the ADFG sequence and three-dimensional structure
is highly conserved, DFG-out inhibitors of other kinases may be designed
by specifically targeting the flanking alanine residue with electric
dipoles.