4QP1

Crystal structure of ERK2 in complex with N-cyclohexyl-9H-purin-6-amine

4QP1 の概要

• エントリーDOI: 10.2210/pdb4qp1/pdb
• 関連するPDBエントリー: 4QP2 4QP3 4QP4 4QP6 4QP7 4QP8 4QP9 4QPA
• 分子名称: Mitogen-activated protein kinase 1, N-BENZYL-9H-PURIN-6-AMINE, IMIDAZOLE, ... (4 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, spindle : P28482
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85844.32

構造登録者

Yin, J.,Wang, W. (登録日: 2014-06-22, 公開日: 2015-09-23, 最終更新日: 2015-12-16)

主引用文献

Burdick, D.J.,Wang, S.,Heise, C.,Pan, B.,Drummond, J.,Yin, J.,Goeser, L.,Magnuson, S.,Blaney, J.,Moffat, J.,Wang, W.,Chen, H.
Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors.
Bioorg.Med.Chem.Lett., 25:4728-4732, 2015

PubMed Abstract: A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency.

PubMed: 26338362
DOI: 10.1016/j.bmcl.2015.08.048

実験手法

X-RAY DIFFRACTION (2.7 Å)