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| | ==Mouse Cereblon thalidomide binding domain complexed with S-form thalidomide== | | ==Mouse Cereblon thalidomide binding domain complexed with S-form thalidomide== |
| - | <StructureSection load='5yj0' size='340' side='right' caption='[[5yj0]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='5yj0' size='340' side='right'caption='[[5yj0]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5yj0]] is a 16 chain structure with sequence from [http://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=5YJ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YJ0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5yj0]] is a 16 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=5YJ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5YJ0 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=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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wx2|3wx2]], [[5yiz|5yiz]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EF2:S-THALIDOMIDE'>EF2</scene>, <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 ([http://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=5yj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yj0 OCA], [https://pdbe.org/5yj0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5yj0 RCSB], [https://www.ebi.ac.uk/pdbsum/5yj0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5yj0 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=5yj0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5yj0 OCA], [http://pdbe.org/5yj0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5yj0 RCSB], [http://www.ebi.ac.uk/pdbsum/5yj0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5yj0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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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| | </div> | | </div> |
| | <div class="pdbe-citations 5yj0" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5yj0" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Hakoshima, T]] | + | [[Category: Mus musculus]] |
| - | [[Category: Mori, T]] | + | [[Category: Hakoshima T]] |
| - | [[Category: Metal binding protein]] | + | [[Category: Mori T]] |
| - | [[Category: Zinc binding protein]]
| + | |
| 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
Thalidomide possesses two optical isomers which have been reported to exhibit different pharmacological and toxicological activities. However, the precise mechanism by which the two isomers exert their different activities remains poorly understood. Here, we present structural and biochemical studies of (S)- and (R)-enantiomers bound to the primary target of thalidomide, cereblon (CRBN). Our biochemical studies employed deuterium-substituted thalidomides to suppress optical isomer conversion, and established that the (S)-enantiomer exhibited ~10-fold stronger binding to CRBN and inhibition of self-ubiquitylation compared to the (R)-enantiomer. The crystal structures of the thalidomide-binding domain of CRBN bound to each enantiomer show that both enantiomers bind the tri-Trp pocket, although the bound form of the (S)-enantiomer exhibited a more relaxed glutarimide ring conformation. The (S)-enantiomer induced greater teratogenic effects on fins of zebrafish compared to the (R)-enantiomer. This study has established a mechanism by which thalidomide exerts its effects in a stereospecific manner at the atomic level.
Structural basis of thalidomide enantiomer binding to cereblon.,Mori T, Ito T, Liu S, Ando H, Sakamoto S, Yamaguchi Y, Tokunaga E, Shibata N, Handa H, Hakoshima T Sci Rep. 2018 Jan 22;8(1):1294. doi: 10.1038/s41598-018-19202-7. PMID:29358579[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mori T, Ito T, Liu S, Ando H, Sakamoto S, Yamaguchi Y, Tokunaga E, Shibata N, Handa H, Hakoshima T. Structural basis of thalidomide enantiomer binding to cereblon. Sci Rep. 2018 Jan 22;8(1):1294. doi: 10.1038/s41598-018-19202-7. PMID:29358579 doi:http://dx.doi.org/10.1038/s41598-018-19202-7
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