View source for 6tfz


==Crystal Structure of EGFR T790M/V948R in Complex with Covalent Pyrrolopyrimidine 19==
<StructureSection load='6tfz' size='340' side='right'caption='[[6tfz]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6tfz]] 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=6TFZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TFZ 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=N7B:~{N}-[2-(2-hydroxyethyloxy)-5-[4-[[1-(phenylmethyl)indazol-5-yl]amino]-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide'>N7B</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6tfz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tfz OCA], [https://pdbe.org/6tfz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tfz RCSB], [https://www.ebi.ac.uk/pdbsum/6tfz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tfz 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 ==
Mutated or amplified Her2 serves as a driver of non-small cell lung cancer (NSCLC) or mediates resistance toward the inhibition of its family member EGFR (epidermal growth factor receptor) with small-molecule inhibitors. Current data from clinical candidates revealed that inhibitors targeting Her2 suffer from poor response rates of less than 40%, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion (ADME) parameters, as well as MS experiments and western blot analysis substantiated our approach.

Targeting Her2-insYVMA with Covalent Inhibitors - A Focused Compound Screening and Structure-Based Design Approach.,Lategahn J, Hardick J, Grabe T, Niggenaber J, Jeyakumar K, Keul M, Tumbrink HL, Becker C, Hodson L, Kirschner T, Klovekorn P, Ketzer J, Baumann M, Terheyden S, Unger A, Weisner J, Muller MP, van Otterlo WAL, Bauer S, Rauh D J Med Chem. 2020 Sep 15. doi: 10.1021/acs.jmedchem.0c00870. PMID:32931277<ref>PMID:32931277</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6tfz" 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: Mueller MP]]
[[Category: Niggenaber J]]
[[Category: Rauh D]]