PDBsum entry 4k33

Transferase

PDB id: 4k33

Contents

Protein chain

293 a.a.

Ligands

ACP

Metals

_MG ×2

Waters ×124

PDB id:

4k33

Name:

Transferase

Title:

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

Structure:

Fibroblast growth factor receptor 3. Chain: a. Fragment: human fgf receptor 3 kinase domain. Synonym: fgfr-3. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr3, jtk4. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.34Å R-factor: 0.181 R-free: 0.228

Authors:

Z.Huang,H.Chen,M.Mohammadi

Key ref:

Z.Huang et al. (2013). Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation. Structure, 21, 1889-1896. PubMed id: 23972473 DOI: 10.1016/j.str.2013.07.017

Date:

10-Apr-13 Release date: 11-Sep-13

Protein chain

P22607  (FGFR3_HUMAN) -  Fibroblast growth factor receptor 3 from Homo sapiens

Seq: 806 a.a.

Struc: 293 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = ACP) matches with 81.25% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.str.2013.07.017

Structure 21:1889-1896 (2013)

PubMed id: 23972473

Structural mimicry of a-loop tyrosine phosphorylation by a pathogenic FGF receptor 3 mutation.

Z.Huang, H.Chen, S.Blais, T.A.Neubert, X.Li, M.Mohammadi.

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.