Journal
STRUCTURE
Volume 21, Issue 10, Pages 1889-1896Publisher
CELL PRESS
DOI: 10.1016/j.str.2013.07.017
Keywords
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Funding
- National Institute of Dental and Craniofacial Research grant [DE13686]
- National Institute of Neurological Disorders and Stroke grant [P30 NS050276]
- Natural Science Foundation of China [31270789, 81102486]
- Zhejiang Key Group Project in Scientific Innovation [2010R10042-01]
- New York Structural Biology Consortium
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The K650E gain-of-function mutation in the tyrosine kinase domain of FGF receptor 3 (FGFR3) causes Thanatophoric Dysplasia type II, a neonatal lethal congenital dwarfism syndrome, and when acquired somatically, it contributes to carcinogenesis. In this report, we determine the crystal structure of the FGFR3 kinase domain harboring this pathogenic mutation and show that the mutation introduces a network of intramolecular hydrogen bonds to stabilize the active-state conformation. In the crystal, the mutant FGFR3 kinases are caught in the act of trans-phosphorylation on a kinase insert autophosphorylation site, emphasizing the fact that the K650E mutation circumvents the requirement for A-loop tyrosine phosphorylation in kinase activation. Analysis of this trans-phosphorylation complex sheds light onto the determinants of tyrosine transphosphorylation specificity. We propose that the targeted inhibition of this pathogenic FGFR3 kinase may be achievable by small molecule kinase inhibitors that selectively bind the active-state conformation of FGFR3 kinase.
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