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==Crystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib== | ==Crystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib== | ||
<StructureSection load='6lud' size='340' side='right'caption='[[6lud]]' scene=''> | <StructureSection load='6lud' size='340' side='right'caption='[[6lud]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LUD OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6lud]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LUD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LUD FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YY3:N-(2-{[2-(DIMETHYLAMINO)ETHYL](METHYL)AMINO}-4-METHOXY-5-{[4-(1-METHYL-1H-INDOL-3-YL)PYRIMIDIN-2-YL]AMINO}PHENYL)PROP-2-ENAMIDE'>YY3</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EGFR, ERBB, ERBB1, HER1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></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=6lud FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lud OCA], [https://pdbe.org/6lud PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lud RCSB], [https://www.ebi.ac.uk/pdbsum/6lud PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lud ProSAT]</span></td></tr> | |||
</table> | </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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6lud" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chiba T]] | [[Category: Receptor protein-tyrosine kinase]] | ||
[[Category: Endo M]] | [[Category: Chiba, T]] | ||
[[Category: Fukami | [[Category: Endo, M]] | ||
[[Category: Kashima K]] | [[Category: Fukami, T A]] | ||
[[Category: Kawauchi H]] | [[Category: Kashima, K]] | ||
[[Category: Sakamoto H]] | [[Category: Kawauchi, H]] | ||
[[Category: Sato S]] | [[Category: Sakamoto, H]] | ||
[[Category: Torizawa T]] | [[Category: Sato, S]] | ||
[[Category: Torizawa, T]] | |||
[[Category: Inhibitor]] | |||
[[Category: Protein kinase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||