View source for 8ou5


==Cereblon isoform 4 in complex with novel Benzamide-Type Cereblon Binder 11b==
<StructureSection load='8ou5' size='340' side='right'caption='[[8ou5]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ou5]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Magnetospirillum_gryphiswaldense Magnetospirillum gryphiswaldense]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OU5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OU5 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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=W1X:4-azanyl-~{N}-[(3~{S})-2,6-bis(oxidanylidene)piperidin-3-yl]-2-(trifluoromethyl)benzamide'>W1X</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=8ou5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ou5 OCA], [https://pdbe.org/8ou5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ou5 RCSB], [https://www.ebi.ac.uk/pdbsum/8ou5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ou5 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A4TVL0_9PROT A4TVL0_9PROT] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ou5" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Magnetospirillum gryphiswaldense]]
[[Category: Bischof L]]
[[Category: Hartmann MD]]
[[Category: Heim C]]