PDBsum entry 3ky2

Transferase

PDB id: 3ky2

Contents

Protein chains

307 a.a.

280 a.a.

Ligands

SO4 ×4

Waters ×247

References listed in PDB file

Key reference

Title

Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells.

Authors

J.H.Bae, T.J.Boggon, F.Tomé, V.Mandiyan, I.Lax, J.Schlessinger.

Ref.

Proc Natl Acad Sci U S A, 2010, 107, 2866-2871. [DOI no: 10.1073/pnas.0914157107]

PubMed id

20133753

Abstract

Tyrosine autophosphorylation of receptor tyrosine kinases plays a critical role in regulation of kinase activity and in recruitment and activation of intracellular signaling pathways. Autophosphorylation is mediated by a sequential and precisely ordered intermolecular (trans) reaction. In this report we present structural and biochemical experiments demonstrating that formation of an asymmetric dimer between activated FGFR1 kinase domains is required for transphosphorylation of FGFR1 in FGF-stimulated cells. Transphosphorylation is mediated by specific asymmetric contacts between the N-lobe of one kinase molecule, which serves as an active enzyme, and specific docking sites on the C-lobe of a second kinase molecule, which serves a substrate. Pathological loss-of-function mutations or oncogenic activating mutations in this interface may hinder or facilitate asymmetric dimer formation and transphosphorylation, respectively. The experiments presented in this report provide the molecular basis underlying the control of transphosphorylation of FGF receptors and other receptor tyrosine kinases.

Figure 1.
The overall structure of asymmetric activated FGFR1 kinase dimer and detailed views of inter receptor contacts. (A) Asymmetric dimer of active phosphorylated FGFR1 is shown in ribbon diagram. Molecules E and S of the asymmetric dimer are colored in cyan and green, respectively. (B) A detailed view of the interface formed between kinases in the asymmetric dimer. ATP analog (AMP-PCP) and interacting residues are shown in stick representation and the magnesium ion is shown as a blue sphere. Residues from molecule S are labeled with primes. The color scheme applied in this figure is used for all figures. Secondary structures are labeled in blue. (C) Surface representation of molecule E is depicted in cyan with interacting residues of the molecule S in stick and ribbon representation. Representative residues from molecule S are labeled. (D) Surface representation of molecule S is shown in green with interacting residues of molecule E (Pale Cyan) in stick and ribbon representation (www.pymol.org).

Figure 4.
The structures of kinase domains of (A) wt-FGFR1 (PDB ID: 3KY2), (B) FGFR1-RE mutant (PDB ID: 3KXX), and (C) activated FGFR1 (FGFR1-3P) (PDB ID: 3GQI) in a simplified cartoon (Upper) and in a ribbon diagram (Below). The catalytic loop is shown in yellow, and the activation loop in green, helix αC is depicted as a cylinder in the cartoon. Phosphotyrosines are colored in red in the cartoon and in stick representation in the ribbon diagram. (D) Ribbon diagrams of kinase insert loops of FGFR1, FGFR1-RE, and FGFR1-3P are in green, cyan, and blue, respectively. Side chains of R576, R577 and R577E are shown in stick representation. (E) Superposition of kinase insert regions of FGFR1 (Green), FGFR1-RE (Cyan), and FGFR1-3P (Blue) revealing multiple conformations of the kinase insert regions in the three structures.