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==Crystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(5)==
==Crystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(5)==
<StructureSection load='5x2c' size='340' side='right' caption='[[5x2c]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
<StructureSection load='5x2c' size='340' side='right'caption='[[5x2c]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5x2c]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X2C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5X2C FirstGlance]. <br>
<table><tr><td colspan='2'>[[5x2c]] is a 2 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=5X2C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5X2C FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7XR:9-cyclopentyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-phenyl-purine-2,8-diamine'>7XR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5x26|5x26]], [[5x27|5x27]], [[5x28|5x28]], [[5x2a|5x2a]], [[5x2f|5x2f]], [[5x2k|5x2k]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7XR:9-cyclopentyl-N2-[4-(4-methylpiperazin-1-yl)phenyl]-N8-phenyl-purine-2,8-diamine'>7XR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EGFR, ERBB, ERBB1, HER1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5x2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x2c OCA], [https://pdbe.org/5x2c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5x2c RCSB], [https://www.ebi.ac.uk/pdbsum/5x2c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5x2c ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5x2c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x2c OCA], [http://pdbe.org/5x2c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x2c RCSB], [http://www.ebi.ac.uk/pdbsum/5x2c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x2c ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[http://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.  
[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 ==
== Function ==
[[http://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>
[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 ==
Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.


Structural insights into drug development strategy targeting EGFR T790M/C797S.,Zhu SJ, Zhao P, Yang J, Ma R, Yan XE, Yang SY, Yang JW, Yun CH Oncotarget. 2018 Jan 10;9(17):13652-13665. doi: 10.18632/oncotarget.24113., eCollection 2018 Mar 2. PMID:29568384<ref>PMID:29568384</ref>
==See Also==
 
*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5x2c" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Yun, C H]]
[[Category: Yun CH]]
[[Category: Egfr]]
[[Category: Sklb]]
[[Category: T790m]]
[[Category: Transferase]]
[[Category: V948r]]

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