PDB 4K33 deposited: 2013-04-10 modified: 2013-10-30
Title Crystal Strucure of FGF Receptor 3 (FGFR3) Kinase Domain Harboring the K650E Mutation, a Gain-of-Function Mutation Responsible for Thanatophoric Dysplasia Type II and Spermatocytic Seminoma
Authors Blais, S., Chen, H., Huang, Z., Li, X., Mohammadi, M., Neubert, T.A.
Structure factors resolution 2.3405 rfactor 0.1755 rfree 0.2278
DPI 0.59 theoretical min: 0.27

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 trans-phosphorylation 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.

Structure 2013 Oct; 21(10):1889-1896 doi:10.1016/j.str.2013.07.017

Cross References
Database source Identifier Description
PubMed 23972473 STRUE6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4K33/0 4K33 0 monomer 0 1 3 2236