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| | ==Structure of the DDB1-CRBN E3 ubiquitin ligase bound to thalidomide== | | ==Structure of the DDB1-CRBN E3 ubiquitin ligase bound to thalidomide== |
| - | <StructureSection load='4ci1' size='340' side='right' caption='[[4ci1]], [[Resolution|resolution]] 2.98Å' scene=''> | + | <StructureSection load='4ci1' size='340' side='right'caption='[[4ci1]], [[Resolution|resolution]] 2.98Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ci1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CI1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ci1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CI1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CI1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EF2:S-THALIDOMIDE'>EF2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.98Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene>, <scene name='pdbligand=EF2:S-THALIDOMIDE'>EF2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ci2|4ci2]], [[4ci3|4ci3]]</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=4ci1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci1 OCA], [https://pdbe.org/4ci1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ci1 RCSB], [https://www.ebi.ac.uk/pdbsum/4ci1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci1 ProSAT]</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=4ci1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ci1 OCA], [http://pdbe.org/4ci1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ci1 RCSB], [http://www.ebi.ac.uk/pdbsum/4ci1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ci1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> [[http://www.uniprot.org/uniprot/CRBN_CHICK CRBN_CHICK]] 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. May also be involved in memory and learning (By similarity). | + | [https://www.uniprot.org/uniprot/CRBN_CHICK CRBN_CHICK] 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. May also be involved in memory and learning (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ci1" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ci1" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[DNA damage-binding protein|DNA damage-binding protein]] |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Boehm, K]] | + | [[Category: Gallus gallus]] |
| - | [[Category: Fischer, E S]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Thoma, N H]] | + | [[Category: Large Structures]] |
| - | [[Category: Cont]] | + | [[Category: Boehm K]] |
| - | [[Category: Dna binding protein-protein binding complex]] | + | [[Category: Fischer ES]] |
| - | [[Category: Dna binding protein-protein complex]] | + | [[Category: Thoma NH]] |
| - | [[Category: Ubiquitin]]
| + | |
| Structural highlights
Function
CRBN_CHICK 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. May also be involved in memory and learning (By similarity).
Publication Abstract from PubMed
In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4CRBN. Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4CRBN and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide.,Fischer ES, Bohm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, Tichkule RB, Schebesta M, Forrester WC, Schirle M, Hassiepen U, Ottl J, Hild M, Beckwith RE, Harper JW, Jenkins JL, Thoma NH Nature. 2014 Jul 16. doi: 10.1038/nature13527. PMID:25043012[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fischer ES, Bohm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, Tichkule RB, Schebesta M, Forrester WC, Schirle M, Hassiepen U, Ottl J, Hild M, Beckwith RE, Harper JW, Jenkins JL, Thoma NH. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014 Jul 16. doi: 10.1038/nature13527. PMID:25043012 doi:http://dx.doi.org/10.1038/nature13527
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