6s8a

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(New page: '''Unreleased structure''' The entry 6s8a is ON HOLD until Paper Publication Authors: Niggenaber, J., Mueller, M.P., Rauh, D. Description: Crystal Structure of EGFR-T790M/C797S in Comp...)
Current revision (12:37, 24 January 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 6s8a is ON HOLD until Paper Publication
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==Crystal Structure of EGFR-T790M/C797S in Complex with Covalent Pyrrolopyrimidine 19h==
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<StructureSection load='6s8a' size='340' side='right'caption='[[6s8a]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6s8a]] 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=6S8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S8A FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L0N:~{N}-[3-[6-[4-(4-methylpiperazin-1-yl)phenyl]-4-(2-methylpropoxy)-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide'>L0N</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6s8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s8a OCA], [https://pdbe.org/6s8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s8a RCSB], [https://www.ebi.ac.uk/pdbsum/6s8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s8a ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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.
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== Function ==
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.
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Authors: Niggenaber, J., Mueller, M.P., Rauh, D.
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Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S.,Lategahn J, Keul M, Klovekorn P, Tumbrink HL, Niggenaber J, Muller MP, Hodson L, Flasshoff M, Hardick J, Grabe T, Engel J, Schultz-Fademrecht C, Baumann M, Ketzer J, Muhlenberg T, Hiller W, Gunther G, Unger A, Muller H, Heimsoeth A, Golz C, Blank-Landeshammer B, Kollipara L, Zahedi RP, Strohmann C, Hengstler JG, van Otterlo WAL, Bauer S, Rauh D Chem Sci. 2019 Oct 4;10(46):10789-10801. doi: 10.1039/c9sc03445e. eCollection, 2019 Dec 14. PMID:31857889<ref>PMID:31857889</ref>
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Description: Crystal Structure of EGFR-T790M/C797S in Complex with covalent Pyrrolopyrimide 2b
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Niggenaber, J]]
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<div class="pdbe-citations 6s8a" style="background-color:#fffaf0;"></div>
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[[Category: Mueller, M.P]]
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[[Category: Rauh, D]]
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==See Also==
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*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Mueller MP]]
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[[Category: Niggenaber J]]
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[[Category: Rauh D]]

Current revision

Crystal Structure of EGFR-T790M/C797S in Complex with Covalent Pyrrolopyrimidine 19h

PDB ID 6s8a

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