View source for 6lub


==Crystal Structure of EGFR(L858R/T790M/C797S) in complex with CH7233163==
<StructureSection load='6lub' size='340' side='right'caption='[[6lub]], [[Resolution|resolution]] 2.31&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6lub]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LUB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.315&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EUX:N-[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]-7-(4-methylpiperazin-1-yl)-5-propan-2-yl-9-[2,2,2-tris(fluoranyl)ethoxy]pyrido[4,3-b]indol-3-amine'>EUX</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6lub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lub OCA], [https://pdbe.org/6lub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lub RCSB], [https://www.ebi.ac.uk/pdbsum/6lub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lub ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[https://omim.org/entry/211980 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 ==
[https://www.uniprot.org/uniprot/EGFR_HUMAN 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.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref>   Isoform 2 may act as an antagonist of EGF action.<ref>PMID:7657591</ref> <ref>PMID:11602604</ref> <ref>PMID:12873986</ref> <ref>PMID:10805725</ref> <ref>PMID:11116146</ref> <ref>PMID:11483589</ref> <ref>PMID:17115032</ref> <ref>PMID:21258366</ref> <ref>PMID:12297050</ref> <ref>PMID:12620237</ref> <ref>PMID:15374980</ref> <ref>PMID:19560417</ref> <ref>PMID:20837704</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (eg. EAI-045) which potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (eg. L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19 and L858R) over wild-type (WT). Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's alphaC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

CH7233163 overcomes osimertinib resistant EGFR-Del19/T790M/C797S mutation.,Kashima K, Kawauchi H, Tanimura H, Tachibana Y, Chiba T, Torizawa T, Sakamoto H Mol Cancer Ther. 2020 Sep 17. pii: 1535-7163.MCT-20-0229. doi:, 10.1158/1535-7163.MCT-20-0229. PMID:32943545<ref>PMID:32943545</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6lub" style="background-color:#fffaf0;"></div>

==See Also==
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chiba T]]
[[Category: Endo M]]
[[Category: Fukami TA]]
[[Category: Kashima K]]
[[Category: Kawauchi H]]
[[Category: Sakamoto H]]
[[Category: Sato S]]
[[Category: Torizawa T]]