5HID

BRAF Kinase domain b3aC loop deletion mutant in complex with AZ628

5HID の概要

• エントリーDOI: 10.2210/pdb5hid/pdb
• 関連するPDBエントリー: 5HI2 5HIE
• 分子名称: Serine/threonine-protein kinase B-raf, 3-(2-cyanopropan-2-yl)-N-{4-methyl-3-[(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}benzamide, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 65833.40

構造登録者

Whalen, D.M.,Foster, S.A.,Ozen, A.,Wongchenko, M.,Yin, J.,Schaefer, G.,Mayfield, J.,Chmielecki, J.,Stephens, P.,Albacker, L.,Yan, Y.,Song, K.,Hatzivassiliou, G.,Eigenbrot, C.,Yu, C.,Shaw, A.S.,Manning, G.,Skelton, N.J.,Hymowitz, S.G.,Malek, S. (登録日: 2016-01-11, 公開日: 2016-04-06, 最終更新日: 2023-09-27)

主引用文献

Foster, S.A.,Whalen, D.M.,Ozen, A.,Wongchenko, M.J.,Yin, J.,Yen, I.,Schaefer, G.,Mayfield, J.D.,Chmielecki, J.,Stephens, P.J.,Albacker, L.A.,Yan, Y.,Song, K.,Hatzivassiliou, G.,Eigenbrot, C.,Yu, C.,Shaw, A.S.,Manning, G.,Skelton, N.J.,Hymowitz, S.G.,Malek, S.
Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.
Cancer Cell, 29:477-493, 2016

PubMed Abstract: Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.

PubMed: 26996308
DOI: 10.1016/j.ccell.2016.02.010

実験手法

X-RAY DIFFRACTION (2.5 Å)