5hxb
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Cereblon in complex with DDB1, CC-885, and GSPT1== |
| + | <StructureSection load='5hxb' size='340' side='right' caption='[[5hxb]], [[Resolution|resolution]] 3.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5hxb]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HXB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HXB FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=85C:1-(3-CHLORO-4-METHYLPHENYL)-3-({2-[(3S)-2,6-DIOXOPIPERIDIN-3-YL]-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-5-YL}METHYL)UREA'>85C</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5hxb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hxb OCA], [http://pdbe.org/5hxb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hxb RCSB], [http://www.ebi.ac.uk/pdbsum/5hxb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hxb ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/CRBN_HUMAN CRBN_HUMAN]] Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ERF3A_HUMAN ERF3A_HUMAN]] Involved in translation termination in response to the termination codons UAA, UAG and UGA. Stimulates the activity of ERF1. Involved in regulation of mammalian cell growth. Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. [[http://www.uniprot.org/uniprot/CRBN_HUMAN CRBN_HUMAN]] Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.<ref>PMID:18414909</ref> <ref>PMID:20223979</ref> [[http://www.uniprot.org/uniprot/DDB1_HUMAN DDB1_HUMAN]] Required for DNA repair. Binds to DDB2 to form the UV-damaged DNA-binding protein complex (the UV-DDB complex). The UV-DDB complex may recognize UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair. The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches. Also appears to function as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1. DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage. The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair. DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR). May also play a role in ubiquitination of CDKN1B/p27kip when associated with CUL4 and SKP2.<ref>PMID:12732143</ref> <ref>PMID:15448697</ref> <ref>PMID:14739464</ref> <ref>PMID:15882621</ref> <ref>PMID:16260596</ref> <ref>PMID:16482215</ref> <ref>PMID:17079684</ref> <ref>PMID:16407242</ref> <ref>PMID:16407252</ref> <ref>PMID:16678110</ref> <ref>PMID:16940174</ref> <ref>PMID:17041588</ref> <ref>PMID:16473935</ref> <ref>PMID:18593899</ref> <ref>PMID:18381890</ref> <ref>PMID:18332868</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBN E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation. | ||
| - | + | A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase.,Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, Fang W, Wang NY, Nguyen D, Houston J, Carmel G, Tran T, Riley M, Nosaka L, Lander GC, Gaidarova S, Xu S, Ruchelman AL, Handa H, Carmichael J, Daniel TO, Cathers BE, Lopez-Girona A, Chamberlain PP Nature. 2016 Jun 22. doi: 10.1038/nature18611. PMID:27338790<ref>PMID:27338790</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5hxb" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Chamberlain, P P]] | ||
| + | [[Category: Matyskiela, M]] | ||
| + | [[Category: Pagarigan, B]] | ||
| + | [[Category: Cereblon]] | ||
| + | [[Category: Crbn]] | ||
| + | [[Category: Crl4]] | ||
| + | [[Category: Cullin]] | ||
| + | [[Category: Dcaf]] | ||
| + | [[Category: Ddb1]] | ||
| + | [[Category: E3]] | ||
| + | [[Category: Gspt1]] | ||
| + | [[Category: Imid]] | ||
| + | [[Category: Ligase]] | ||
| + | [[Category: Ubiquitin]] | ||
Revision as of 18:32, 12 July 2016
Cereblon in complex with DDB1, CC-885, and GSPT1
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Categories: Chamberlain, P P | Matyskiela, M | Pagarigan, B | Cereblon | Crbn | Crl4 | Cullin | Dcaf | Ddb1 | E3 | Gspt1 | Imid | Ligase | Ubiquitin
