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3pfv

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{{STRUCTURE_3pfv| PDB=3pfv | SCENE= }}
 
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===Crystal structure of Cbl-b TKB domain in complex with EGFR pY1069 peptide===
 
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==Disease==
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==Crystal structure of Cbl-b TKB domain in complex with EGFR pY1069 peptide==
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[[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.
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<StructureSection load='3pfv' size='340' side='right'caption='[[3pfv]], [[Resolution|resolution]] 2.27&Aring;' scene=''>
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== Structural highlights ==
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==Function==
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<table><tr><td colspan='2'>[[3pfv]] 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=3PFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PFV FirstGlance]. <br>
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[[http://www.uniprot.org/uniprot/CBLB_HUMAN CBLB_HUMAN]] E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization.<ref>PMID:10022120</ref> <ref>PMID:10086340</ref> <ref>PMID:11087752</ref> <ref>PMID:11526404</ref> [[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>
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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]] 2.27&#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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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==About this Structure==
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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=3pfv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pfv OCA], [https://pdbe.org/3pfv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pfv RCSB], [https://www.ebi.ac.uk/pdbsum/3pfv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pfv ProSAT]</span></td></tr>
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[[3pfv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PFV OCA].
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CBLB_HUMAN CBLB_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization.<ref>PMID:10022120</ref> <ref>PMID:10086340</ref> <ref>PMID:11087752</ref> <ref>PMID:11526404</ref>
==See Also==
==See Also==
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*[[Ubiquitin protein ligase|Ubiquitin protein ligase]]
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<references group="xtra"/><references/>
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__TOC__
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[[Category: Human]]
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</StructureSection>
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[[Category: Arrowsmith, C H.]]
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[[Category: Homo sapiens]]
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[[Category: Ayinampudi, V.]]
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[[Category: Large Structures]]
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[[Category: Bountra, C.]]
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[[Category: Arrowsmith CH]]
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[[Category: Bullock, A.]]
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[[Category: Ayinampudi V]]
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[[Category: Canning, P.]]
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[[Category: Bountra C]]
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[[Category: Chaikuad, A.]]
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[[Category: Bullock A]]
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[[Category: Cooper, C D.O.]]
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[[Category: Canning P]]
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[[Category: Delft, F von.]]
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[[Category: Chaikuad A]]
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[[Category: Edwards, A M.]]
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[[Category: Cooper CDO]]
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[[Category: Gileadi, O.]]
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[[Category: Edwards AM]]
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[[Category: Guo, K.]]
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[[Category: Gileadi O]]
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[[Category: Krojer, T.]]
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[[Category: Guo K]]
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[[Category: Muniz, J R.C.]]
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[[Category: Krojer T]]
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[[Category: SGC, Structural Genomics Consortium.]]
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[[Category: Muniz JRC]]
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[[Category: Vollmar, M.]]
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[[Category: Vollmar M]]
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[[Category: Weigelt, J.]]
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[[Category: Weigelt J]]
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[[Category: Cbl-b]]
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[[Category: Von Delft F]]
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[[Category: Ligase-protein binding complex]]
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[[Category: Sgc]]
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[[Category: Sh3-binding protein]]
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[[Category: Signal transduction protein]]
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[[Category: Structural genomic]]
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[[Category: Structural genomics consortium]]
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Current revision

Crystal structure of Cbl-b TKB domain in complex with EGFR pY1069 peptide

PDB ID 3pfv

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