3buo

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[[Image:3buo.png|left|200px]]
 
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{{STRUCTURE_3buo| PDB=3buo | SCENE= }}
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==Crystal structure of c-Cbl-TKB domain complexed with its binding motif in EGF receptor'==
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<StructureSection load='3buo' size='340' side='right'caption='[[3buo]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3buo]] is a 4 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=3BUO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BUO 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=PTR:O-PHOSPHOTYROSINE'>PTR</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=3buo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3buo OCA], [https://pdbe.org/3buo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3buo RCSB], [https://www.ebi.ac.uk/pdbsum/3buo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3buo 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/bu/3buo_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=3buo 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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The c-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.
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===Crystal structure of c-Cbl-TKB domain complexed with its binding motif in EGF receptor'===
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Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.,Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J EMBO J. 2008 Mar 5;27(5):804-16. Epub 2008 Feb 14. PMID:18273061<ref>PMID:18273061</ref>
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{{ABSTRACT_PUBMED_18273061}}
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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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==About this Structure==
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<div class="pdbe-citations 3buo" style="background-color:#fffaf0;"></div>
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[[3buo]] is a 4 chain structure of [[Epidermal Growth Factor Receptor]] 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=3BUO OCA].
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==See Also==
==See Also==
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*[[Epidermal Growth Factor Receptor|Epidermal Growth Factor Receptor]]
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*[[Epidermal growth factor receptor 3D structures|Epidermal growth factor receptor 3D structures]]
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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==Reference==
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== References ==
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<ref group="xtra">PMID:018273061</ref><references group="xtra"/>
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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: Buschdorf, J P.]]
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[[Category: Large Structures]]
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[[Category: Guy, G R.]]
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[[Category: Buschdorf JP]]
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[[Category: Jackson, R A.]]
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[[Category: Guy GR]]
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[[Category: Ng, C.]]
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[[Category: Jackson RA]]
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[[Category: Sivaraman, J.]]
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[[Category: Ng C]]
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[[Category: Sun, Q.]]
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[[Category: Sivaraman J]]
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[[Category: Anti-oncogene]]
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[[Category: Sun Q]]
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[[Category: Atp-binding]]
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[[Category: Cbl]]
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[[Category: Cell cycle]]
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[[Category: Complex]]
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[[Category: Disease mutation]]
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[[Category: Glycoprotein]]
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[[Category: Kinase]]
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[[Category: Ligase]]
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[[Category: Ligase-signaling protein complex]]
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[[Category: Membrane]]
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[[Category: Metal-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: Phosphoprotein]]
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[[Category: Proto-oncogene]]
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[[Category: Receptor]]
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[[Category: Secreted]]
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[[Category: Sh2 domain]]
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[[Category: Signal transduction]]
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[[Category: Tkb]]
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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: Ubl conjugation pathway]]
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[[Category: Zinc-finger]]
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Current revision

Crystal structure of c-Cbl-TKB domain complexed with its binding motif in EGF receptor'

PDB ID 3buo

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