4K33

Crystal Structure 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

Summary for 4K33

• Entry DOI: 10.2210/pdb4k33/pdb
• Related: 2PSQ 2PVF 4J97
• Descriptor: Fibroblast growth factor receptor 3, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: kinase domain fold consisting of n- and c-lobes, receptor tyrosine kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane ; Single-pass type I membrane protein . Isoform 3: Secreted. Isoform 4: Cell membrane ; Single-pass type I membrane protein : P22607
• Total number of polymer chains: 1
• Total formula weight: 37222.80

Authors

Huang, Z.,Chen, H.,Mohammadi, M. (deposition date: 2013-04-10, release date: 2013-09-11, Last modification date: 2023-09-20)

Primary citation

Huang, Z.,Chen, H.,Blais, S.,Neubert, T.A.,Li, X.,Mohammadi, M.
Structural Mimicry of A-Loop Tyrosine Phosphorylation by a Pathogenic FGF Receptor 3 Mutation.
Structure, 21:1889-1896, 2013

PubMed 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.

PubMed: 23972473
DOI: 10.1016/j.str.2013.07.017

Experimental method

X-RAY DIFFRACTION (2.3405 Å)