1m17

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(New page: 200px<br /> <applet load="1m17" size="450" color="white" frame="true" align="right" spinBox="true" caption="1m17, resolution 2.60&Aring;" /> '''Epidermal Growth Fa...)
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[[Image:1m17.gif|left|200px]]<br />
 
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<applet load="1m17" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1m17, resolution 2.60&Aring;" />
 
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'''Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib'''<br />
 
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==Overview==
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==Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib==
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The crystal structure of the kinase domain from the epidermal growth, factor receptor (EGFRK) including forty amino acids from the, carboxyl-terminal tail has been determined to 2.6-A resolution, both with, and without an EGFRK-specific inhibitor currently in Phase III clinical, trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other, known receptor tyrosine kinases in possessing constitutive kinase activity, without a phosphorylation event within their kinase domains. Despite its, lack of phosphorylation, we find that the EGFRK activation loop adopts a, conformation similar to that of the phosphorylated active form of the, kinase domain from the insulin receptor. Surprisingly, key residues of a, putative dimerization motif lying between the EGFRK domain and, carboxyl-terminal substrate docking sites are found in close contact with, the kinase domain. Significant intermolecular contacts involving the, carboxyl-terminal tail are discussed with respect to receptor, oligomerization.
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<StructureSection load='1m17' size='340' side='right'caption='[[1m17]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1m17]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The June 2010 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Epidermal Growth Factor Receptor'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2010_6 10.2210/rcsb_pdb/mom_2010_6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M17 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M17 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=AQ4:[6,7-BIS(2-METHOXY-ETHOXY)QUINAZOLINE-4-YL]-(3-ETHYNYLPHENYL)AMINE'>AQ4</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=1m17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m17 OCA], [https://pdbe.org/1m17 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m17 RCSB], [https://www.ebi.ac.uk/pdbsum/1m17 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m17 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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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/m1/1m17_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1m17 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known diseases associated with this structure: Adenocarcinoma of lung, response to tyrosine kinase inhibitor in OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=131550 131550]], Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=131550 131550]], Nonsmall cell lung cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=131550 131550]]
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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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==About this Structure==
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<references/>
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1M17 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with AQ4 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1M17 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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[[Category: Epidermal Growth Factor Receptor]]
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Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor., Stamos J, Sliwkowski MX, Eigenbrot C, J Biol Chem. 2002 Nov 29;277(48):46265-72. Epub 2002 Aug 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12196540 12196540]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Transferase]]
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[[Category: RCSB PDB Molecule of the Month]]
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[[Category: Eigenbrot, C.]]
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[[Category: Eigenbrot C]]
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[[Category: Sliwkowski, M.X.]]
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[[Category: Sliwkowski MX]]
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[[Category: Stamos, J.]]
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[[Category: Stamos J]]
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[[Category: AQ4]]
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[[Category: transferase]]
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[[Category: tyrosine kinase domain]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:06:05 2007''
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Current revision

Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib

PDB ID 1m17

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