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PDBsum entry 4zsg
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References listed in PDB file
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Key reference
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Title
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Discovery of a novel allosteric inhibitor-Binding site in erk5: comparison with the canonical kinase hinge ATP-Binding site.
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Authors
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H.Chen,
J.Tucker,
X.Wang,
P.R.Gavine,
C.Phillips,
M.A.Augustin,
P.Schreiner,
S.Steinbacher,
M.Preston,
D.Ogg.
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Ref.
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Acta Crystallogr D Struct Biol, 2016,
72,
682-693.
[DOI no: ]
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PubMed id
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Abstract
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MAP kinases act as an integration point for multiple biochemical signals and are
involved in a wide variety of cellular processes such as proliferation,
differentiation, regulation of transcription and development. As a member of the
MAP kinase family, ERK5 (MAPK7) is involved in the downstream signalling
pathways of various cell-surface receptors, including receptor tyrosine kinases
and G protein-coupled receptors. In the current study, five structures of the
ERK5 kinase domain co-crystallized with ERK5 inhibitors are reported.
Interestingly, three of the compounds bind at a novel allosteric binding site in
ERK5, while the other two bind at the typical ATP-binding site. Binding of
inhibitors at the allosteric site is accompanied by displacement of the P-loop
into the ATP-binding site and is shown to be ATP-competitive in an enzymatic
assay of ERK5 kinase activity. Kinase selectivity data show that the most potent
allosteric inhibitor exhibits superior kinase selectivity compared with the two
inhibitors that bind at the canonical ATP-binding site. An analysis of these
structures and comparison with both a previously published ERK5-inhibitor
complex structure (PDB entry 4b99) and the structures of three other kinases
(CDK2, ITK and MEK) in complex with allosteric inhibitors are presented.
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