PDBsum entry 5hic

Transferase/transferase inhibitor

PDB id: 5hic

Contents

Protein chain

302 a.a.

Ligands

SO4

63N

Waters ×99

PDB id:

5hic

Name:

Transferase/transferase inhibitor

Title:

Egfr kinase domain mutant "tmlr" with a imidazopyridinyl- aminopyrimidine inhibitor

Structure:

Epidermal growth factor receptor. Chain: a. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.60Å R-factor: 0.191 R-free: 0.233

Authors:

C.Eigenbrot,C.Yu

Key ref:

S.A.Foster et al. (2016). Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2. Cancer Cell, 29, 477-493. PubMed id: 26996308 DOI: 10.1016/j.ccell.2016.02.010

Date:

11-Jan-16 Release date: 06-Apr-16

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 302 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.ccell.2016.02.010

Cancer Cell 29:477-493 (2016)

PubMed id: 26996308

Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.

S.A.Foster, D.M.Whalen, A.Özen, M.J.Wongchenko, J.Yin, I.Yen, G.Schaefer, J.D.Mayfield, J.Chmielecki, P.J.Stephens, L.A.Albacker, Y.Yan, K.Song, G.Hatzivassiliou, C.Eigenbrot, C.Yu, A.S.Shaw, G.Manning, N.J.Skelton, S.G.Hymowitz, S.Malek.

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.