8dey
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Ternary complex structure of Cereblon-DDB1 bound to IKZF2(ZF2,3) and the molecular glue DKY709== |
| + | <StructureSection load='8dey' size='340' side='right'caption='[[8dey]], [[Resolution|resolution]] 3.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8dey]] 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=8DEY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DEY 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]] 3.7Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LWK:(3~{S})-3-[3-oxidanylidene-6-[1-(phenylmethyl)piperidin-4-yl]-1~{H}-isoindol-2-yl]piperidine-2,6-dione'>LWK</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=8dey FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dey OCA], [https://pdbe.org/8dey PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dey RCSB], [https://www.ebi.ac.uk/pdbsum/8dey PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dey 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 == | ||
| + | Malignant tumors can evade destruction by the immune system by attracting immune-suppressive regulatory T cells (Treg) cells. The IKZF2 (Helios) transcription factor plays a crucial role in maintaining function and stability of Treg cells, and IKZF2 deficiency reduces tumor growth in mice. Here we report the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2 that spares IKZF1/3. We describe the recruitment-guided medicinal chemistry campaign leading to NVP-DKY709 that redirected the degradation selectivity of cereblon (CRBN) binders from IKZF1 toward IKZF2. Selectivity of NVP-DKY709 for IKZF2 was rationalized by analyzing the DDB1:CRBN:NVP-DKY709:IKZF2(ZF2 or ZF2-3) ternary complex X-ray structures. Exposure to NVP-DKY709 reduced the suppressive activity of human Treg cells and rescued cytokine production in exhausted T-effector cells. In vivo, treatment with NVP-DKY709 delayed tumor growth in mice with a humanized immune system and enhanced immunization responses in cynomolgus monkeys. NVP-DKY709 is being investigated in the clinic as an immune-enhancing agent for cancer immunotherapy. | ||
| - | + | Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy.,Bonazzi S, d'Hennezel E, Beckwith REJ, Xu L, Fazal A, Magracheva A, Ramesh R, Cernijenko A, Antonakos B, Bhang HC, Caro RG, Cobb JS, Ornelas E, Ma X, Wartchow CA, Clifton MC, Forseth RR, Fortnam BH, Lu H, Csibi A, Tullai J, Carbonneau S, Thomsen NM, Larrow J, Chie-Leon B, Hainzl D, Gu Y, Lu D, Meyer MJ, Alexander D, Kinyamu-Akunda J, Sabatos-Peyton CA, Dales NA, Zecri FJ, Jain RK, Shulok J, Wang YK, Briner K, Porter JA, Tallarico JA, Engelman JA, Dranoff G, Bradner JE, Visser M, Solomon JM Cell Chem Biol. 2023 Mar 16;30(3):235-247.e12. doi: , 10.1016/j.chembiol.2023.02.005. Epub 2023 Mar 1. PMID:36863346<ref>PMID:36863346</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8dey" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Clifton MC]] | ||
| + | [[Category: Ma X]] | ||
| + | [[Category: Ornelas E]] | ||
Current revision
Ternary complex structure of Cereblon-DDB1 bound to IKZF2(ZF2,3) and the molecular glue DKY709
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