7MPH

GRB2 SH2 Domain with Compound 7

7MPH の概要

• エントリーDOI: 10.2210/pdb7mph/pdb
• 分子名称: Growth factor receptor-bound protein 2, (4-{(10R,11E,14S,18S)-18-(2-amino-2-oxoethyl)-14-[(naphthalen-1-yl)methyl]-8,17,20-trioxo-7,16,19-triazaspiro[5.14]icos-11-en-10-yl}phenyl)acetic acid, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, growth factor receptor, ras-mapk signaling cascade, protein binding
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 71830.90

構造登録者

Sun, L.,Schonbrunn, E. (登録日: 2021-05-04, 公開日: 2021-09-22, 最終更新日: 2023-10-18)

主引用文献

Xiao, T.,Sun, L.,Zhang, M.,Li, Z.,Haura, E.B.,Schonbrunn, E.,Ji, H.
Synthesis and structural characterization of a monocarboxylic inhibitor for GRB2 SH2 domain.
Bioorg.Med.Chem.Lett., 51:128354-128354, 2021

PubMed Abstract: A monocarboxylic inhibitor was designed and synthesized to disrupt the protein-protein interaction (PPI) between GRB2 and phosphotyrosine-containing proteins. Biochemical characterizations show compound 7 binds with the Src homology 2 (SH2) domain of GRB2 and is more potent than EGFR phosphopeptide 14-mer. X-ray crystallographic studies demonstrate compound 7 occupies the GRB2 binding site for phosphotyrosine-containing sequences and reveal key structural features for GRB2-inhibitor binding. This compound with a -1 formal charge offers a new direction for structural optimization to generate cell-permeable inhibitors for this key protein target of the aberrant Ras-MAPK signaling cascade.

PubMed: 34506932
DOI: 10.1016/j.bmcl.2021.128354

実験手法

X-RAY DIFFRACTION (2 Å)