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2itz

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[[Image:2itz.jpg|left|200px]]
 
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{{Structure
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==Crystal structure of EGFR kinase domain L858R mutation in complex with Iressa==
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|PDB= 2itz |SIZE=350|CAPTION= <scene name='initialview01'>2itz</scene>, resolution 2.80&Aring;
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<StructureSection load='2itz' size='340' side='right'caption='[[2itz]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
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|SITE= <scene name='pdbsite=AC1:Cl+Binding+Site+For+Residue+A+2020'>AC1</scene> and <scene name='pdbsite=AC2:Ire+Binding+Site+For+Residue+A+2021'>AC2</scene>
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IRE:3-CHLORO-4-FLUORO-N-[(4Z)-7-METHOXY-6-(3-MORPHOLIN-4-YLPROPOXY)QUINAZOLIN-4(1H)-YLIDENE]ANILINE'>IRE</scene>
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<table><tr><td colspan='2'>[[2itz]] 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=2ITZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ITZ FirstGlance]. <br>
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|ACTIVITY= <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>
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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]] 2.8&#8491;</td></tr>
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|GENE=
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IRE:GEFITINIB'>IRE</scene></td></tr>
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|DOMAIN=
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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=2itz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2itz OCA], [https://pdbe.org/2itz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2itz RCSB], [https://www.ebi.ac.uk/pdbsum/2itz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2itz ProSAT]</span></td></tr>
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|RELATEDENTRY=[[1dnq|1DNQ]], [[1dnr|1DNR]], [[1ivo|1IVO]], [[1m14|1M14]], [[1m17|1M17]], [[1mox|1MOX]], [[1nql|1NQL]], [[1xkk|1XKK]], [[1yy9|1YY9]], [[1z9i|1Z9I]], [[2itn|2ITN]], [[2itp|2ITP]], [[2itq|2ITQ]], [[2itt|2ITT]], [[2itu|2ITU]], [[2itv|2ITV]], [[2itw|2ITW]], [[2itx|2ITX]], [[2ito|2ITO]], [[2ity|2ITY]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2itz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2itz OCA], [http://www.ebi.ac.uk/pdbsum/2itz PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2itz RCSB]</span>
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== Disease ==
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}}
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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/it/2itz_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=2itz ConSurf].
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<div style="clear:both"></div>
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'''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH IRESSA'''
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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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==Overview==
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<references/>
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Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788, and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme.
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__TOC__
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</StructureSection>
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==About this Structure==
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2ITZ is a [[Single protein]] structure of 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=2ITZ OCA].
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==Reference==
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Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity., Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ, Cancer Cell. 2007 Mar;11(3):217-27. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17349580 17349580]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Receptor protein-tyrosine kinase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Boggon TJ]]
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[[Category: Boggon, T J.]]
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[[Category: Eck MJ]]
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[[Category: Eck, M J.]]
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[[Category: Greulich H]]
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[[Category: Greulich, H.]]
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[[Category: Li Y]]
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[[Category: Li, Y.]]
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[[Category: Meyerson M]]
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[[Category: Meyerson, M.]]
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[[Category: Woo S]]
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[[Category: Woo, S.]]
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[[Category: Yun C-H]]
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[[Category: Yun, C H.]]
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[[Category: alternative splicing]]
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[[Category: anti-oncogene]]
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[[Category: atp-binding]]
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[[Category: cell cycle]]
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[[Category: disease mutation]]
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[[Category: egfr]]
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[[Category: epidermal growth factor]]
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[[Category: gefitinib]]
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[[Category: glycoprotein]]
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[[Category: iressa]]
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[[Category: l858r]]
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[[Category: membrane]]
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[[Category: nucleotide-binding]]
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[[Category: phosphorylation]]
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[[Category: polymorphism]]
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[[Category: receptor]]
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[[Category: transferase]]
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[[Category: transmembrane]]
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[[Category: tyrosine-protein kinase]]
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[[Category: zd1839]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:48:35 2008''
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Current revision

Crystal structure of EGFR kinase domain L858R mutation in complex with Iressa

PDB ID 2itz

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