1xkk

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[[Image:1xkk.png|left|200px]]
 
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==EGFR kinase domain complexed with a quinazoline inhibitor- GW572016==
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The line below this paragraph, containing "STRUCTURE_1xkk", creates the "Structure Box" on the page.
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<StructureSection load='1xkk' size='340' side='right'caption='[[1xkk]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[1xkk]] 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=1XKK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XKK FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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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]] 2.4&#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=FMM:N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINAZOLINAMINE'>FMM</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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{{STRUCTURE_1xkk| PDB=1xkk | SCENE= }}
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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=1xkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xkk OCA], [https://pdbe.org/1xkk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xkk RCSB], [https://www.ebi.ac.uk/pdbsum/1xkk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xkk 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/xk/1xkk_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=1xkk ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.
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===EGFR kinase domain complexed with a quinazoline inhibitor- GW572016===
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A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells.,Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980<ref>PMID:15374980</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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The line below this paragraph, {{ABSTRACT_PUBMED_15374980}}, adds the Publication Abstract to the page
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<div class="pdbe-citations 1xkk" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 15374980 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15374980}}
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==About this Structure==
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[[1xkk]] is a 1 chain structure of [[Epidermal Growth Factor Receptor]] with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The June 2010 RCSB PDB [http://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 [http://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=1XKK OCA].
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==See Also==
==See Also==
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*[[Epidermal Growth Factor Receptor]]
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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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==Reference==
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<references/>
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<ref group="xtra">PMID:15374980</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Epidermal Growth Factor Receptor]]
[[Category: Epidermal Growth Factor Receptor]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Large Structures]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: RCSB PDB Molecule of the Month]]
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[[Category: Transferase]]
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[[Category: Alligood KJ]]
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[[Category: Alligood, K J.]]
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[[Category: Dickerson SH]]
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[[Category: Dickerson, S H.]]
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[[Category: Ellis B]]
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[[Category: Ellis, B.]]
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[[Category: Gilmer TM]]
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[[Category: Gilmer, T M.]]
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[[Category: Hassell A]]
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[[Category: Hassell, A.]]
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[[Category: Horne E]]
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[[Category: Horne, E.]]
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[[Category: Lackey K]]
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[[Category: Lackey, K.]]
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[[Category: McDonald OB]]
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[[Category: McDonald, O B.]]
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[[Category: Pennisi C]]
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[[Category: Pennisi, C.]]
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[[Category: Rusnak DW]]
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[[Category: Rusnak, D W.]]
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[[Category: Shewchuk LM]]
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[[Category: Shewchuk, L M.]]
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[[Category: Truesdale AT]]
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[[Category: Truesdale, A T.]]
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[[Category: Wood ER]]
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[[Category: Wood, E R.]]
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[[Category: Yuan D]]
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[[Category: Yuan, D.]]
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[[Category: Egfr]]
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[[Category: Epidermal growth factor receptor]]
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[[Category: Kinase]]
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[[Category: Transferase]]
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Current revision

EGFR kinase domain complexed with a quinazoline inhibitor- GW572016

PDB ID 1xkk

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