5HID

BRAF Kinase domain b3aC loop deletion mutant in complex with AZ628

Summary for 5HID

• Entry DOI: 10.2210/pdb5hid/pdb
• Related: 5HI2 5HIE
• Descriptor: 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)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P15056
• Total number of polymer chains: 2
• Total formula weight: 65833.40

Authors

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. (deposition date: 2016-01-11, release date: 2016-04-06, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)