5XGM

Crystal structure of EGFR 696-1022 T790M in complex with Go6976

5XGM の概要

• エントリーDOI: 10.2210/pdb5xgm/pdb
• 関連するPDBエントリー: 5XGN
• 分子名称: Epidermal growth factor receptor, 12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole (3 entities in total)
• 機能のキーワード: egfr t790m, go6976, 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 membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38029.02

構造登録者

Kong, L.L.,Yun, C.H. (登録日: 2017-04-14, 公開日: 2017-10-11, 最終更新日: 2023-11-22)

主引用文献

Kong, L.L.,Ma, R.,Yao, M.Y.,Yan, X.E.,Zhu, S.J.,Zhao, P.,Yun, C.H.
Structural pharmacological studies on EGFR T790M/C797S.
Biochem. Biophys. Res. Commun., 488:266-272, 2017

PubMed Abstract: Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR. In the present work, we reported the complex crystal structures of EGFR T790M/C797S + Gö6976 and T790M + Gö6976, along with enzyme kinetic data of EGFR wild-type, T790M and T790M/C797S. These data showed that the C797S mutation does not significantly alter the structure and function of the EGFR kinase, but increases the local hydrophilicity around residue 797. The complex crystal structures also elucidated the detailed binding mode of Gö6976 to EGFR and explained why this compound prefers binding to T790M mutant. These structural pharmacological data would facilitate future drug development studies.

PubMed: 28456628
DOI: 10.1016/j.bbrc.2017.04.138

実験手法

X-RAY DIFFRACTION (2.952 Å)