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Acta Crystallogr D Struct Biol. 2016 May;72(Pt 5):682-93. doi: 10.1107/S2059798316004502. Epub 2016 Apr 26.

Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site.

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Chemistry Innovation Centre, Discovery Sciences, AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden.
Structure and Biophysics, Discovery Sciences, AstraZeneca R&D Alderley Park, Macclesfield SK10 4TG, England.
Innovation Centre China, AstraZeneca Asia and Emerging Markets iMed, Shanghai 201203, People's Republic of China.
Proteros biostructures GmbH, Bunsenstrasse 7a, 82152 Martinsried, Germany.
Screening Sciences, Discovery Sciences, AstraZeneca R&D Alderley Park, Macclesfield SK10 4TG, England.


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.


ERK5 kinase; MAPK7 kinase; allosteric kinase inhibitor; crystal structure

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