PDBsum entry 2jkk

Transferase

PDB id: 2jkk

Contents

Protein chain

258 a.a. *

Ligands

SO4

BI9

Waters ×139

* Residue conservation analysis

PDB id:

2jkk

Name:

Transferase

Title:

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

Structure:

Focal adhesion kinase 1. Chain: a. Fragment: kinase domain, residues 411-686. Synonym: 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:

2.00Å R-factor: 0.182 R-free: 0.236

Authors:

D.Lietha,M.J.Eck

Key ref:

D.Lietha and M.J.Eck (2008). Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation. Plos One, 3, e3800. PubMed id: 19030106

Date:

28-Aug-08 Release date: 09-Sep-08

Protein chain

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

Seq: 1053 a.a.

Struc: 258 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

Plos One 3:e3800 (2008)

PubMed id: 19030106

Crystal structures of the FAK kinase in complex with TAE226 and related bis-anilino pyrimidine inhibitors reveal a helical DFG conformation.

D.Lietha, M.J.Eck.

ABSTRACT

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase required for cell migration, proliferation and survival. FAK overexpression has been documented in diverse human cancers and is associated with a poor clinical outcome. Recently, a novel bis-anilino pyrimidine inhibitor, TAE226, was reported to efficiently inhibit FAK signaling, arrest tumor growth and invasion and prolong the life of mice with glioma or ovarian tumor implants. Here we describe the crystal structures of the FAK kinase bound to TAE226 and three related bis-anilino pyrimidine compounds. TAE226 induces a conformation of the N-terminal portion of the kinase activation loop that is only observed in FAK, but is distinct from the conformation in both the active and inactive states of the kinase. This conformation appears to require a glycine immediately N-terminal to the "DFG motif", which adopts a helical conformation stabilized by interactions with TAE226. The presence of a glycine residue in this position contributes to the specificity of TAE226 and related compounds for FAK. Our work highlights the fact that kinases can access conformational space that is not necessarily utilized for their native catalytic regulation, and that such conformations can explain and be exploited for inhibitor specificity.