View source for 8u17


==The ternary complex structure of DDB1-CRBN-SALL4(ZF1,2)-long bound to Pomalidomide==
<StructureSection load='8u17' size='340' side='right'caption='[[8u17]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8u17]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8U17 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8U17 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.1&#8491;</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8u17 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8u17 OCA], [https://pdbe.org/8u17 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8u17 RCSB], [https://www.ebi.ac.uk/pdbsum/8u17 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8u17 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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 ==
[https://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 ==
The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4.

Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon.,Ma X, Leon B, Ornelas E, Dovala D, Tandeske L, Luu C, Pardee G, Widger S, Solomon JM, Beckwith REJ, Moser H, Clifton MC, Wartchow CA Sci Rep. 2023 Dec 12;13(1):22088. doi: 10.1038/s41598-023-48606-3. PMID:38086859<ref>PMID:38086859</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8u17" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Clifton MC]]
[[Category: Ma X]]
[[Category: Ornelas E]]