7er2: Difference between revisions
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New page: '''Unreleased structure''' The entry 7er2 is ON HOLD Authors: Zhu, S.J., Yun, C.H. Description: Crystal structure of EGFR 696-1022 T790M/C797S in complex with LS_2_40 [[Category: Unrel... |
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The | ==Crystal structure of EGFR 696-1022 T790M/C797S in complex with LS_2_40== | ||
<StructureSection load='7er2' size='340' side='right'caption='[[7er2]], [[Resolution|resolution]] 2.66Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7er2]] 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=7ER2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ER2 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]] 2.662Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JAU:5-chloranyl-N2-[3-chloranyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine'>JAU</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=7er2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7er2 OCA], [https://pdbe.org/7er2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7er2 RCSB], [https://www.ebi.ac.uk/pdbsum/7er2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7er2 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 == | |||
A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR(T790M/C797S) inhibitors. One of the most potent and selective compounds 18k strongly suppressed the EGFR(L858R/T790M/C797S) and EGFR(19Del/T790M/C797S) kinases with IC50 values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFR(T790M/C797S) mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR(T790M/C797S) with a close derivative 18f was solved to provide insight on the inhibitor's binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization. | |||
Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR(T790M/C797S) Mutants.,Li S, Zhang T, Zhu SJ, Lei C, Lai M, Peng L, Tong L, Pang Z, Lu X, Ding J, Ren X, Yun CH, Xie H, Ding K ACS Med Chem Lett. 2022 Jan 7;13(2):196-202. doi: 10.1021/acsmedchemlett.1c00555., eCollection 2022 Feb 10. PMID:35178175<ref>PMID:35178175</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Yun | <div class="pdbe-citations 7er2" style="background-color:#fffaf0;"></div> | ||
[[Category: Zhu | |||
==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: Yun CH]] | |||
[[Category: Zhu SJ]] | |||
