5hib

EGFR kinase domain mutant "TMLR" with a pyrazolopyrimidine inhibitorEGFR kinase domain mutant "TMLR" with a pyrazolopyrimidine inhibitor

Structural highlights 5hib is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Related: 5hic Gene: EGFR, ERBB, ERBB1, HER1 (HUMAN) Activity: Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [EGFR_HUMAN] Defects in EGFR are associated with lung cancer (LNCR) [MIM:211980]. LNCR is a common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. Function [EGFR_HUMAN] Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TGFA/TGF-alpha, amphiregulin, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules. May also activate the NF-kappa-B signaling cascade. Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin. Isoform 2 may act as an antagonist of EGF action. Publication Abstract from PubMed 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 beta3-alphaC 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 alphaC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the alphaC "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. Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2.,Foster SA, Whalen DM, Ozen A, Wongchenko MJ, Yin J, Yen I, Schaefer G, Mayfield JD, Chmielecki J, Stephens PJ, Albacker LA, Yan Y, Song K, Hatzivassiliou G, Eigenbrot C, Yu C, Shaw AS, Manning G, Skelton NJ, Hymowitz SG, Malek S Cancer Cell. 2016 Apr 11;29(4):477-93. doi: 10.1016/j.ccell.2016.02.010. Epub, 2016 Mar 17. PMID:26996308 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 5hib, resolution 2.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image