9htp: Difference between revisions
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==Cereblon isoform 4 from Magnetospirillum gryphiswaldense in complex with glutarimide based compound 2p== | |||
<StructureSection load='9htp' size='340' side='right'caption='[[9htp]], [[Resolution|resolution]] 2.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9htp]] 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=9HTP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HTP 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]] 2.35Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IW5:(3~{S})-3-[methyl(phenyl)amino]piperidine-2,6-dione'>A1IW5</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=9htp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9htp OCA], [https://pdbe.org/9htp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9htp RCSB], [https://www.ebi.ac.uk/pdbsum/9htp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9htp ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/A4TVL0_9PROT A4TVL0_9PROT] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In this work we present an easy, one-step synthetic protocol to explore a large chemical space of glutarimide-based cereblon (CRBN) ligands for targeted protein degradation. It is built upon our recently suggested approach to generating structurally diverse series of alpha-substituted glutarimide derivatives through an efficient Rh(II)-catalyzed X-H insertion reaction of 3-diazopiperidine-2,6-dione, with moderate to high yields. In total, 25 glutarimide derivatives incorporating variable side chains were synthesized and evaluated in vitro. All ligands showed a favorable lipophilicity, and several were able to outperform the binding affinity of thalidomide as a reference. In addition, most compounds showed low intrinsic cytotoxicity in myeloma cell lines and human peripheral blood mononuclear cells, and did not recruit canonical neosubstrates. A cellular thermal shift assay further demonstrated that the most potent analogs stabilize CRBN in live cells, confirming their on-target engagement. The development of the series was accompanied by a crystallographic study, which rationalizes the observed improvements in binding affinity and neosubstrate selectivity, and can support further development towards molecular glue activity and PROTACs design. | |||
Extending the chemical space of glutarimide-based cereblon ligands through an efficient Rh(II)-catalyzed X-H insertion reaction.,Levashova E, Bischof L, Bunev A, Sapegin A, Grygor'eva O, Kudinov A, Ebeling S, Tatarinov I, Dar'in D, Kantin G, Hartmann MD, Kalinin S Eur J Med Chem. 2025 Oct 3;301:118235. doi: 10.1016/j.ejmech.2025.118235. PMID:41086529<ref>PMID:41086529</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9htp" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Magnetospirillum gryphiswaldense]] | |||
[[Category: Bischof L]] | |||
[[Category: Hartmann MD]] | |||
