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Conformational Analysis of the DFG-Out Kinase Motif and Biochemical Profiling of Structurally Validated Type II Inhibitors
journal contribution
posted on 2015-12-17, 06:48 authored by R. S.
K. Vijayan, Peng He, Vivek Modi, Krisna
C. Duong-Ly, Haiching Ma, Jeffrey R. Peterson, Roland L. Dunbrack, Ronald M. LevyStructural
coverage of the human kinome has been steadily increasing
over time. The structures provide valuable insights into the molecular
basis of kinase function and also provide a foundation for understanding
the mechanisms of kinase inhibitors. There are a large number of kinase
structures in the PDB for which the Asp and Phe of the DFG motif on
the activation loop swap positions, resulting in the formation of
a new allosteric pocket. We refer to these structures as “classical
DFG-out” conformations in order to distinguish them from conformations
that have also been referred to as DFG-out in the literature but that
do not have a fully formed allosteric pocket. We have completed a
structural analysis of almost 200 small molecule inhibitors bound
to classical DFG-out conformations; we find that they are recognized
by both type I and type II inhibitors. In contrast, we find that nonclassical
DFG-out conformations strongly select against type II inhibitors because
these structures have not formed a large enough allosteric pocket
to accommodate this type of binding mode. In the course of this study
we discovered that the number of structurally validated type II inhibitors
that can be found in the PDB and that are also represented in publicly
available biochemical profiling studies of kinase inhibitors is very
small. We have obtained new profiling results for several additional
structurally validated type II inhibitors identified through our conformational
analysis. Although the available profiling data for type II inhibitors
is still much smaller than for type I inhibitors, a comparison of
the two data sets supports the conclusion that type II inhibitors
are more selective than type I. We comment on the possible contribution
of the DFG-in to DFG-out conformational reorganization to the selectivity.