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| | + | '''Unreleased structure''' |
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| - | ==Cereblon isoform 4 in complex with novel Benzamide-Type Cereblon Binder 11c==
| + | The entry 8ou6 is ON HOLD until Paper Publication |
| - | <StructureSection load='8ou6' size='340' side='right'caption='[[8ou6]], [[Resolution|resolution]] 1.84Å' scene=''>
| + | |
| - | == Structural highlights ==
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| - | <table><tr><td colspan='2'>[[8ou6]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Magnetospirillum_gryphiswaldense_MSR-1_v2 Magnetospirillum gryphiswaldense MSR-1 v2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OU6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OU6 FirstGlance]. <br>
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| - | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.84Å</td></tr>
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| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=W26:4-azanyl-~{N}-[(3~{S})-2,6-bis(oxidanylidene)piperidin-3-yl]-2-methyl-benzamide'>W26</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ou6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ou6 OCA], [https://pdbe.org/8ou6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ou6 RCSB], [https://www.ebi.ac.uk/pdbsum/8ou6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ou6 ProSAT]</span></td></tr>
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| - | </table>
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| - | == Function ==
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| - | [https://www.uniprot.org/uniprot/A4TVL0_9PROT A4TVL0_9PROT]
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| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds.
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| - | Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs.,Steinebach C, Bricelj A, Murgai A, Sosic I, Bischof L, Ng YLD, Heim C, Maiwald S, Proj M, Voget R, Feller F, Kosmrlj J, Sapozhnikova V, Schmidt A, Zuleeg MR, Lemnitzer P, Mertins P, Hansen FK, Gutschow M, Kronke J, Hartmann MD J Med Chem. 2023 Nov 9;66(21):14513-14543. doi: 10.1021/acs.jmedchem.3c00851. , Epub 2023 Oct 30. PMID:37902300<ref>PMID:37902300</ref>
| + | Authors: |
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | Description: |
| - | </div>
| + | [[Category: Unreleased Structures]] |
| - | <div class="pdbe-citations 8ou6" style="background-color:#fffaf0;"></div>
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| - | == References ==
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| - | <references/>
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| - | __TOC__
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| - | </StructureSection>
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| - | [[Category: Large Structures]] | + | |
| - | [[Category: Magnetospirillum gryphiswaldense MSR-1 v2]]
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| - | [[Category: Bischof L]]
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| - | [[Category: Hartmann MD]]
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| - | [[Category: Heim C]]
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