2gs2

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[[Image:2gs2.gif|left|200px]]
 
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{{Structure
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==Crystal Structure of the active EGFR kinase domain==
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|PDB= 2gs2 |SIZE=350|CAPTION= <scene name='initialview01'>2gs2</scene>, resolution 2.800&Aring;
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<StructureSection load='2gs2' size='340' side='right'caption='[[2gs2]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND=
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<table><tr><td colspan='2'>[[2gs2]] 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=2GS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2GS2 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= EGFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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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=2gs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gs2 OCA], [https://pdbe.org/2gs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2gs2 RCSB], [https://www.ebi.ac.uk/pdbsum/2gs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2gs2 ProSAT]</span></td></tr>
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|DOMAIN=
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</table>
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|RELATEDENTRY=[[2gs6|2GS6]], [[2gs7|2GS7]]
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== Disease ==
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2gs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2gs2 OCA], [http://www.ebi.ac.uk/pdbsum/2gs2 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2gs2 RCSB]</span>
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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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}}
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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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'''Crystal Structure of the active EGFR kinase domain'''
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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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==Overview==
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gs/2gs2_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=2gs2 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 ==
The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization.
The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization.
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==Disease==
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An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.,Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J Cell. 2006 Jun 16;125(6):1137-49. PMID:16777603<ref>PMID:16777603</ref>
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Known disease 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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==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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2GS2 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=2GS2 OCA].
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</div>
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<div class="pdbe-citations 2gs2" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor., Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J, Cell. 2006 Jun 16;125(6):1137-49. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16777603 16777603]
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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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<references/>
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__TOC__
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</StructureSection>
[[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: Cole PA]]
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[[Category: Cole, P A.]]
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[[Category: Gureasko J]]
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[[Category: Gureasko, J.]]
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[[Category: Kuriyan J]]
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[[Category: Kuriyan, J.]]
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[[Category: Shen K]]
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[[Category: Shen, K.]]
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[[Category: Zhang X]]
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[[Category: Zhang, X.]]
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[[Category: active]]
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[[Category: egfr]]
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[[Category: kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:20:47 2008''
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Current revision

Crystal Structure of the active EGFR kinase domain

PDB ID 2gs2

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