4EBV

Structure of Focal Adhesion Kinase catalytic domain in complex with novel allosteric inhibitor

4EBV の概要

• エントリーDOI: 10.2210/pdb4ebv/pdb
• 分子名称: Focal adhesion kinase 1, 8-(4-ethylphenyl)-5-methyl-2,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide, ISOPROPYL ALCOHOL, ... (4 entities in total)
• 機能のキーワード: kinase domain, allosteric inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell junction, focal adhesion: Q05397
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35553.91

構造登録者

Skene, R.J.,Hosfield, D.J. (登録日: 2012-03-25, 公開日: 2012-08-22, 最終更新日: 2024-10-09)

主引用文献

Iwatani, M.,Iwata, H.,Okabe, A.,Skene, R.J.,Tomita, N.,Hayashi, Y.,Aramaki, Y.,Hosfield, D.J.,Hori, A.,Baba, A.,Miki, H.
Discovery and characterization of novel allosteric FAK inhibitors.
Eur.J.Med.Chem., 61:49-60, 2013

PubMed Abstract: Focal adhesion kinase (FAK) regulates cell survival and proliferation pathways. Here we report the discovery of a highly selective series of 1,5-dihydropyrazolo[4,3-c][2,1]benzothiazines that demonstrate a novel mode of allosteric inhibition of FAK. These compounds showed slow dissociation from unphosphorylated FAK and were noncompetitive with ATP after long preincubation. Co-crystal structural analysis revealed that the compounds target a novel allosteric site within the C-lobe of the kinase domain, which induces disruption of ATP pocket formation leading to the inhibition of kinase activity. The potency of allosteric inhibition was reduced by phosphorylation of FAK. Coupled SAR analysis revealed that N-substitution of the fused pyrazole is critical to achieve allosteric binding and high selectivity among kinases.

PubMed: 22819505
DOI: 10.1016/j.ejmech.2012.06.035

実験手法

X-RAY DIFFRACTION (1.67 Å)