PDBsum entry 4d58

Transferase

PDB id: 4d58

Contents

Protein chains

255 a.a.

Ligands

SO4 ×3

BI9

Waters ×185

PDB id:

4d58

Name:

Transferase

Title:

Focal adhesion kinase catalytic domain in complex with bis-anilino pyrimidine inhibitor

Structure:

Focal adhesion kinase. Chain: a, b. Fragment: kinase domain, residues 411-686. Synonym: fadk 1, focal adhesion kinase-related nonkinase, frnk, p41/ p43frnk, protein-tyrosine kinase 2, p125fak, pp125fak. Engineered: yes

Source:

Gallus gallus. Chicken. Organism_taxid: 9031. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five.

Resolution:

1.95Å R-factor: 0.197 R-free: 0.228

Authors:

J.Le Coq,A.Lin,D.Lietha

Key ref:

J.Zhou et al. (2015). Allosteric regulation of focal adhesion kinase by PIP₂ and ATP. Biophys J, 108, 698-705. PubMed id: 25650936 DOI: 10.1016/j.bpj.2014.11.3454

Date:

03-Nov-14 Release date: 18-Feb-15

Protein chains

Q00944  (FAK1_CHICK) -  Focal adhesion kinase 1 from Gallus gallus

Seq: 1053 a.a.

Struc: 255 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

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

Added reference

DOI no: 10.1016/j.bpj.2014.11.3454

Biophys J 108:698-705 (2015)

PubMed id: 25650936

Allosteric regulation of focal adhesion kinase by PIP₂ and ATP.

J.Zhou, A.Bronowska, J.Le Coq, D.Lietha, F.Gräter.

ABSTRACT

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that regulates cell signaling, proliferation, migration, and development. A major mechanism of regulation of FAK activity is an intramolecular autoinhibitory interaction between two of its domains-the catalytic and FERM domains. Upon cell adhesion to the extracellular matrix, FAK is being translocated toward focal adhesion sites and activated. Interactions of FAK with phosphoinositide phosphatidylinsositol-4,5-bis-phosphate (PIP2) are required to activate FAK. However, the molecular mechanism of the activation remains poorly understood. Recent fluorescence resonance energy transfer experiments revealed a closure of the FERM-kinase interface upon ATP binding, which is reversed upon additional binding of PIP2. Here, we addressed the allosteric regulation of FAK by performing all-atom molecular-dynamics simulations of a FAK fragment containing the catalytic and FERM domains, and comparing the dynamics in the absence or presence of ATP and PIP2. As a major conformational change, we observe a closing and opening motion upon ATP and additional PIP2 binding, respectively, in good agreement with the fluorescence resonance energy transfer experiments. To reveal how the binding of the regulatory PIP2 to the FERM F2 lobe is transduced to the very distant F1/N-lobe interface, we employed force distribution analysis. We identified a network of mainly charged residue-residue interactions spanning from the PIP2 binding site to the distant interface between the kinase and FERM domains, comprising candidate residues for mutagenesis to validate the predicted mechanism of FAK activation.