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| | <StructureSection load='3wx2' size='340' side='right'caption='[[3wx2]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='3wx2' size='340' side='right'caption='[[3wx2]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3wx2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WX2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3wx2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WX2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3wx1|3wx1]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">Crbn ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=3wx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wx2 OCA], [https://pdbe.org/3wx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wx2 RCSB], [https://www.ebi.ac.uk/pdbsum/3wx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wx2 ProSAT]</span></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=3wx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wx2 OCA], [https://pdbe.org/3wx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wx2 RCSB], [https://www.ebi.ac.uk/pdbsum/3wx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wx2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CRBN_MOUSE CRBN_MOUSE]] 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 (By similarity).
| + | [https://www.uniprot.org/uniprot/CRBN_MOUSE CRBN_MOUSE] 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 (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Hakoshima, T]] | + | [[Category: Hakoshima T]] |
| - | [[Category: Handa, H]] | + | [[Category: Handa H]] |
| - | [[Category: Hirano, Y]] | + | [[Category: Hirano Y]] |
| - | [[Category: Ito, T]] | + | [[Category: Ito T]] |
| - | [[Category: Mori, T]] | + | [[Category: Mori T]] |
| - | [[Category: Yamaguchi, Y]] | + | [[Category: Yamaguchi Y]] |
| - | [[Category: E3 ubiquitin ligase]]
| + | |
| - | [[Category: Metal binding protein]]
| + | |
| - | [[Category: Zinc finger]]
| + | |
| Structural highlights
Function
CRBN_MOUSE 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 (By similarity).
Publication Abstract from PubMed
The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide, therapeutically important drugs for multiple myeloma and other B-cell malignancies. These drugs directly bind Cereblon (CRBN) and promote the recruitment of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading to substrate ubiquitination and degradation. Here we present the crystal structure of human CRBN bound to DDB1 and the drug lenalidomide. A hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide, whereas the isoindolinone ring is exposed to solvent. We also solved the structures of the mouse TBD in the apo state and with thalidomide or pomalidomide. Site-directed mutagenesis in lentiviral-expression myeloma models showed that key drug-binding residues are critical for antiproliferative effects.
Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.,Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, Corral LG, Ren YJ, Wang M, Riley M, Delker SL, Ito T, Ando H, Mori T, Hirano Y, Handa H, Hakoshima T, Daniel TO, Cathers BE Nat Struct Mol Biol. 2014 Aug 10. doi: 10.1038/nsmb.2874. PMID:25108355[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, Corral LG, Ren YJ, Wang M, Riley M, Delker SL, Ito T, Ando H, Mori T, Hirano Y, Handa H, Hakoshima T, Daniel TO, Cathers BE. Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat Struct Mol Biol. 2014 Aug 10. doi: 10.1038/nsmb.2874. PMID:25108355 doi:http://dx.doi.org/10.1038/nsmb.2874
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