2JKQ

Focal Adhesion Kinase catalytic domain in complex with bis-anilino pyrimidine inhibitor

2JKQ の概要

• エントリーDOI: 10.2210/pdb2jkq/pdb
• 関連するPDBエントリー: 1KTM 1PV3 1QVX 2AEH 2AL6 2J0J 2J0K 2J0L 2J0M 2JKK 2JKM 2JKO
• 分子名称: FOCAL ADHESION KINASE 1, 4-(1,4'-bipiperidin-1'-yl)-7-({5-chloro-2-[(2-methoxyphenyl)amino]pyrimidin-4-yl}amino)-2-methyl-2,3-dihydro-1H-isoindol-1-one (3 entities in total)
• 機能のキーワード: transferase, nucleotide-binding, tyrosine-protein kinase, kinase inhibitor, integrin signaling, kinase, atp-binding, cell migration, focal adhesion
• 由来する生物種: GALLUS GALLUS (CHICKEN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32320.87

構造登録者

Lietha, D.,Eck, M.J. (登録日: 2008-08-29, 公開日: 2008-09-09, 最終更新日: 2024-11-06)

主引用文献

Lietha, D.,Eck, M.J.
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-, 2008

PubMed 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.

PubMed: 19030106
DOI: 10.1371/JOURNAL.PONE.0003800

実験手法

X-RAY DIFFRACTION (2.6 Å)