6uml
From Proteopedia
(Difference between revisions)
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==Structural Basis for Thalidomide Teratogenicity Revealed by the Cereblon-DDB1-SALL4-Pomalidomide Complex== | ==Structural Basis for Thalidomide Teratogenicity Revealed by the Cereblon-DDB1-SALL4-Pomalidomide Complex== | ||
| - | <StructureSection load='6uml' size='340' side='right'caption='[[6uml]]' scene=''> | + | <StructureSection load='6uml' size='340' side='right'caption='[[6uml]], [[Resolution|resolution]] 3.58Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UML OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UML FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6uml]] is a 3 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=6UML OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UML FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uml FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uml OCA], [http://pdbe.org/6uml PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uml RCSB], [http://www.ebi.ac.uk/pdbsum/6uml PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uml ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Y70:S-POMALIDOMIDE'>Y70</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DDB1, XAP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CRBN, AD-006 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SALL4, ZNF797 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uml FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uml OCA], [http://pdbe.org/6uml PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uml RCSB], [http://www.ebi.ac.uk/pdbsum/6uml PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uml ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/SALL4_HUMAN SALL4_HUMAN]] Acro-renal-ocular syndrome;IVIC syndrome;Okihiro syndrome due to 20q13 microdeletion;Okihiro syndrome due to a point mutation. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [[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/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/SALL4_HUMAN SALL4_HUMAN]] Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.<ref>PMID:23012367</ref> [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4(CRBN) E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk. | ||
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| + | Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex.,Matyskiela ME, Clayton T, Zheng X, Mayne C, Tran E, Carpenter A, Pagarigan B, McDonald J, Rolfe M, Hamann LG, Lu G, Chamberlain PP Nat Struct Mol Biol. 2020 Apr;27(4):319-322. doi: 10.1038/s41594-020-0405-9. Epub, 2020 Apr 6. PMID:32251415<ref>PMID:32251415</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6uml" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chamberlain | + | [[Category: Chamberlain, P P]] |
| - | [[Category: Clayton | + | [[Category: Clayton, T L]] |
| - | [[Category: Matyskiela | + | [[Category: Matyskiela, M E]] |
| - | [[Category: Pagarigan | + | [[Category: Pagarigan, B E]] |
| - | [[Category: Tran | + | [[Category: Tran, E T]] |
| + | [[Category: C2h2 zinc finger]] | ||
| + | [[Category: Celmod]] | ||
| + | [[Category: Cereblon-crl4]] | ||
| + | [[Category: Ligase]] | ||
| + | [[Category: Ubiquitin ligase]] | ||
Revision as of 06:10, 22 April 2020
Structural Basis for Thalidomide Teratogenicity Revealed by the Cereblon-DDB1-SALL4-Pomalidomide Complex
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