4li5

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{{STRUCTURE_4li5| PDB=4li5 | SCENE= }}
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==EGFR-K IN COMPLEX WITH N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl] Prop-2-enamide==
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===EGFR-K IN COMPLEX WITH N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl] Prop-2-enamide===
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<StructureSection load='4li5' size='340' side='right' caption='[[4li5]], [[Resolution|resolution]] 2.64&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23930994}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4li5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LI5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LI5 FirstGlance]. <br>
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==Disease==
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1WY:N-(3-{[5-CHLORO-4-(1H-INDOL-3-YL)PYRIMIDIN-2-YL]AMINO}-4-METHOXYPHENYL)PROPANAMIDE'>1WY</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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<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 Homo sapiens])</td></tr>
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<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>
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<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=4li5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4li5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4li5 RCSB], [http://www.ebi.ac.uk/pdbsum/4li5 PDBsum]</span></td></tr>
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</table>
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== 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.
[[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.
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A novel series of small molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modelling this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the L858R activating mutant, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH) based assay has been used to measure thiol reactivity towards the electrophilic functionality of the inhibitor series enabling both the identification of a suitable reactivity window for potency and the development of reactivity quantitative structure property relationship (QSPR) to support design.
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==Function==
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Structure and Reactivity Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR).,Ward RA, Anderton M, Ashton S, Bethel P, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross D, Debreczeni JE, Eberlein C, Finlay RV, Hill GB, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ, Grist M J Med Chem. 2013 Aug 9. PMID:23930994<ref>PMID:23930994</ref>
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[[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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4li5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LI5 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:023930994</ref><references group="xtra"/><references/>
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*[[Epidermal Growth Factor Receptor|Epidermal Growth Factor Receptor]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]
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[[Category: Anderton, M.]]
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[[Category: Anderton, M]]
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[[Category: Ashton, S.]]
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[[Category: Ashton, S]]
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[[Category: Augustin, M.]]
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[[Category: Augustin, M]]
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[[Category: Bethel, P.]]
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[[Category: Bethel, P]]
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[[Category: Box, M.]]
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[[Category: Box, M]]
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[[Category: Butterworth, S.]]
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[[Category: Butterworth, S]]
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[[Category: Chroley, C.]]
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[[Category: Chroley, C]]
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[[Category: Chuaqui, C.]]
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[[Category: Chuaqui, C]]
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[[Category: Colclough, N.]]
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[[Category: Colclough, N]]
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[[Category: Cross, D.]]
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[[Category: Cross, D]]
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[[Category: Debreczeni, J E.]]
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[[Category: Debreczeni, J E]]
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[[Category: Eberlein, C.]]
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[[Category: Eberlein, C]]
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[[Category: Finlay, R.]]
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[[Category: Finlay, R]]
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[[Category: Grist, M.]]
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[[Category: Grist, M]]
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[[Category: Hill, G.]]
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[[Category: Hill, G]]
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[[Category: Kiefersauer, R.]]
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[[Category: Kiefersauer, R]]
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[[Category: Klinowska, T.]]
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[[Category: Klinowska, T]]
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[[Category: Lane, C.]]
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[[Category: Lane, C]]
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[[Category: Martin, S.]]
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[[Category: Martin, S]]
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[[Category: Nagel, S.]]
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[[Category: Nagel, S]]
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[[Category: Orme, J.]]
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[[Category: Orme, J]]
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[[Category: Seiffert, G B.]]
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[[Category: Seiffert, G B]]
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[[Category: Smith, P.]]
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[[Category: Smith, P]]
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[[Category: Wang, F.]]
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[[Category: Wang, F]]
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[[Category: Ward, R.]]
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[[Category: Ward, R]]
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[[Category: Waring, M.]]
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[[Category: Waring, M]]
[[Category: Egf receptor kinase]]
[[Category: Egf receptor kinase]]
[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 10:14, 20 January 2015

EGFR-K IN COMPLEX WITH N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl] Prop-2-enamide

4li5, resolution 2.64Å

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