6CAD

Crystal structure of RAF kinase domain bound to the inhibitor 2a

6CAD の概要

• エントリーDOI: 10.2210/pdb6cad/pdb
• 分子名称: Serine/threonine-protein kinase B-raf, 1-(propan-2-yl)-3-({3-[3-(trifluoromethyl)phenyl]isoquinolin-8-yl}ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: braf inhibitors, signaling protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65444.81

構造登録者

Maisonneuve, P.,Kurinov, I.,Assadieskandar, A.,Yu, C.,Liu, X.,Chen, Y.-C.,Prakash, G.K.S.,Zhang, C.,SIcheri, F. (登録日: 2018-01-30, 公開日: 2018-02-21, 最終更新日: 2023-10-04)

主引用文献

Assadieskandar, A.,Yu, C.,Maisonneuve, P.,Liu, X.,Chen, Y.C.,Prakash, G.K.S.,Kurinov, I.,Sicheri, F.,Zhang, C.
Effects of rigidity on the selectivity of protein kinase inhibitors.
Eur J Med Chem, 146:519-528, 2018

PubMed Abstract: Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. Here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors.

PubMed: 29407977
DOI: 10.1016/j.ejmech.2018.01.053

実験手法

X-RAY DIFFRACTION (2.55 Å)