3vrp: Difference between revisions

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==Crystal structure of the tyrosine kinase binding domain of Cbl-c in complex with phospho-EGFR peptide==
==Crystal structure of the tyrosine kinase binding domain of Cbl-c in complex with phospho-EGFR peptide==
<StructureSection load='3vrp' size='340' side='right' caption='[[3vrp]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
<StructureSection load='3vrp' size='340' side='right'caption='[[3vrp]], [[Resolution|resolution]] 1.52&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3vrp]] is a 2 chain structure 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=3VRP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VRP FirstGlance]. <br>
<table><tr><td colspan='2'>[[3vrp]] 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=3VRP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VRP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.52&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3vrn|3vrn]], [[3vro|3vro]], [[3vrq|3vrq]], [[3vrr|3vrr]]</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3vrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vrp OCA], [https://pdbe.org/3vrp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3vrp RCSB], [https://www.ebi.ac.uk/pdbsum/3vrp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3vrp ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CBLC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3vrp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3vrp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3vrp RCSB], [http://www.ebi.ac.uk/pdbsum/3vrp PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/EGFR_HUMAN EGFR_HUMAN]] Defects in EGFR are associated with lung cancer (LNCR) [MIM:[http://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.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/CBLC_HUMAN CBLC_HUMAN]] Regulator of EGFR mediated signal transduction. [[http://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> 
[https://www.uniprot.org/uniprot/CBLC_HUMAN CBLC_HUMAN] Regulator of EGFR mediated signal transduction.
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 3vrp" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Isozaki, Y]]
[[Category: Isozaki Y]]
[[Category: Nakagawa, A]]
[[Category: Nakagawa A]]
[[Category: Suzuki, M]]
[[Category: Suzuki M]]
[[Category: Takeshita, K]]
[[Category: Takeshita K]]
[[Category: Tezuka, T]]
[[Category: Tezuka T]]
[[Category: Yamamoto, T]]
[[Category: Yamamoto T]]
[[Category: Yamanashi, Y]]
[[Category: Yamanashi Y]]
[[Category: Yamashita, E]]
[[Category: Yamashita E]]
[[Category: Calcium-binding ef hand]]
[[Category: Divergent sh2 domain]]
[[Category: Protein binding-transferase complex]]
[[Category: Ptb domain]]
[[Category: Regulator of egfr mediated signal transduction]]
[[Category: Ubiquitously expressed]]

Latest revision as of 12:48, 30 October 2024

Crystal structure of the tyrosine kinase binding domain of Cbl-c in complex with phospho-EGFR peptideCrystal structure of the tyrosine kinase binding domain of Cbl-c in complex with phospho-EGFR peptide

Structural highlights

3vrp is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.52Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CBLC_HUMAN Regulator of EGFR mediated signal transduction.

Publication Abstract from PubMed

Through their ubiquitin ligase activity, Cbl-family proteins suppress signalling mediated by protein-tyrosine kinases (PTKs), but can also function as adaptor proteins to positively regulate signalling. The tyrosine kinase binding (TKB) domain of this family is critical for binding with tyrosine-phosphorylated target proteins. Here, we analysed the crystal structure of the TKB domain of Cbl-c/Cbl-3 (Cbl-c TKB), which is a distinct member of the mammalian Cbl-family. In comparison with Cbl TKB, Cbl-c TKB showed restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB augmenting this flexibility enhanced its binding to target phosphoproteins. These results suggest that proteins, post-translational modifications or mutations that alter structural flexibility of the TKB domain of Cbl-family proteins could regulate their binding to target phosphoproteins and thereby, affect PTK-mediated signalling.

Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c.,Takeshita K, Tezuka T, Isozaki Y, Yamashita E, Suzuki M, Kim M, Yamanashi Y, Yamamoto T, Nakagawa A J Biochem. 2012 Nov;152(5):487-95. doi: 10.1093/jb/mvs085. Epub 2012 Aug 9. PMID:22888118[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Takeshita K, Tezuka T, Isozaki Y, Yamashita E, Suzuki M, Kim M, Yamanashi Y, Yamamoto T, Nakagawa A. Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c. J Biochem. 2012 Nov;152(5):487-95. doi: 10.1093/jb/mvs085. Epub 2012 Aug 9. PMID:22888118 doi:http://dx.doi.org/10.1093/jb/mvs085

3vrp, resolution 1.52Å

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