4ZLO

Serine/threonine-protein kinase PAK1 complexed with a dibenzodiazepine: identification of an allosteric site on PAK1

4ZLO の概要

• エントリーDOI: 10.2210/pdb4zlo/pdb
• 関連するPDBエントリー: 4ZJI 4ZJJ
• 分子名称: Serine/threonine-protein kinase PAK 1, 2,8-difluoro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: dibenzodazepine, pak1, kinase, 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: Cytoplasm: Q13153
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67098.91

構造登録者

Bellamacina, C.R.,Bussiere, D.E. (登録日: 2015-05-01, 公開日: 2015-08-05, 最終更新日: 2024-10-23)

主引用文献

Karpov, A.S.,Amiri, P.,Bellamacina, C.,Bellance, M.H.,Breitenstein, W.,Daniel, D.,Denay, R.,Fabbro, D.,Fernandez, C.,Galuba, I.,Guerro-Lagasse, S.,Gutmann, S.,Hinh, L.,Jahnke, W.,Klopp, J.,Lai, A.,Lindvall, M.K.,Ma, S.,Mobitz, H.,Pecchi, S.,Rummel, G.,Shoemaker, K.,Trappe, J.,Voliva, C.,Cowan-Jacob, S.W.,Marzinzik, A.L.
Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.
Acs Med.Chem.Lett., 6:776-781, 2015

PubMed Abstract: The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels of selectivity across the kinome. Herein we report our structure-based optimization strategy of a dibenzodiazepine hit 1, discovered in a fragment-based screen, yielding highly potent and selective inhibitors of PAK1 such as 2 and 3. Compound 2 was cocrystallized with PAK1 to confirm binding to an allosteric site and to reveal novel key interactions. Compound 3 modulated PAK1 at the cellular level and due to its selectivity enabled valuable research to interrogate biological functions of the PAK1 kinase.

PubMed: 26191365
DOI: 10.1021/acsmedchemlett.5b00102

実験手法

X-RAY DIFFRACTION (2.5 Å)