title: Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation.
abstract: 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.
authors: School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Department of Biochemistry and Molecular Pharmacology New York University School of Medicine, New York, NY 10016, USA.
authors: Zhifeng
authors: Z
authors: Huang
authors: School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.|Department of Biochemistry and Molecular Pharmacology New York University School of Medicine, New York, NY 10016, USA.
authors: Huaibin
authors: H
authors: Chen
authors: Kimmel Center for Biology and Medicine at the Skirball Institute New York University School of Medicine, New York, NY 10016, USA.
authors: Steven
authors: S
authors: Blais
authors: Kimmel Center for Biology and Medicine at the Skirball Institute New York University School of Medicine, New York, NY 10016, USA.
authors: Thomas A
authors: TA
authors: Neubert
authors: School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors: Xiaokun
authors: X
authors: Li
authors: Department of Biochemistry and Molecular Pharmacology New York University School of Medicine, New York, NY 10016, USA.
authors: Moosa
authors: M
authors: Mohammadi
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry* / Q000235:genetics; D012886:Skull / Q000002:abnormalities; D013796:Thanatophoric Dysplasia / Q000235:genetics; D014443:Tyrosine / Q000737:chemistry
chemical_list: D010750:Phosphoproteins; D014443:Tyrosine; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
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