3bun

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(New page: 200px<br /><applet load="3bun" size="350" color="white" frame="true" align="right" spinBox="true" caption="3bun, resolution 2.000&Aring;" /> '''Crystal structure o...)
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[[Image:3bun.jpg|left|200px]]<br /><applet load="3bun" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="3bun, resolution 2.000&Aring;" />
 
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'''Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4'''<br />
 
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==Overview==
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==Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4==
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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 orientates 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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<StructureSection load='3bun' size='340' side='right'caption='[[3bun]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3bun]] is a 2 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=3BUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BUN 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&#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=3bun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bun OCA], [https://pdbe.org/3bun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bun RCSB], [https://www.ebi.ac.uk/pdbsum/3bun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bun ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/SPY4_HUMAN SPY4_HUMAN] Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1.<ref>PMID:12717443</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/3bun_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=3bun 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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==About this Structure==
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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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3BUN is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=3BUN OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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 Feb 14;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18273061 18273061]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 3bun" style="background-color:#fffaf0;"></div>
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[[Category: Protein complex]]
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[[Category: Buschdorf, J P.]]
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[[Category: Guy, G R.]]
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[[Category: Jackson, R A.]]
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[[Category: Ng, C.]]
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[[Category: Sivaraman, J.]]
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[[Category: Sun, Q.]]
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[[Category: alternative splicing]]
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[[Category: calcium]]
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[[Category: cbl]]
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[[Category: complex]]
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[[Category: cytoplasm]]
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[[Category: developmental protein]]
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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: phosphoprotein]]
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[[Category: proto-oncogene]]
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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: ubl conjugation pathway]]
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[[Category: zinc]]
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[[Category: zinc-finger]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 27 07:59:51 2008''
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==See Also==
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Buschdorf JP]]
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[[Category: Guy GR]]
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[[Category: Jackson RA]]
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[[Category: Ng C]]
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[[Category: Sivaraman J]]
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[[Category: Sun Q]]

Current revision

Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4

PDB ID 3bun

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