5HIC

EGFR kinase domain mutant "TMLR" with a imidazopyridinyl-aminopyrimidine inhibitor

Summary for 5HIC

• Entry DOI: 10.2210/pdb5hic/pdb
• Related: 5HIB
• Descriptor: Epidermal growth factor receptor, SULFATE ION, N-{2-[1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl]pyrimidin-4-yl}-1-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-6-amine, ... (4 entities in total)
• Functional Keywords: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 38069.94

Authors

Eigenbrot, C.,Yu, C. (deposition date: 2016-01-11, release date: 2016-04-06, Last modification date: 2024-03-06)

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 (2.6 Å)