View source for 8bur


==Structure of DDB1 bound to DS50-engaged CDK12-cyclin K==
<StructureSection load='8bur' size='340' side='right'caption='[[8bur]], [[Resolution|resolution]] 3.64&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8bur]] is a 9 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=8BUR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BUR 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]] 3.64&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RQU:~{N}-[2-(2-methoxyphenyl)ethyl]-2-[[9-propan-2-yl-6-[(4-pyridin-2-ylphenyl)methylamino]purin-2-yl]amino]ethanamide'>RQU</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=8bur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bur OCA], [https://pdbe.org/8bur PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bur RCSB], [https://www.ebi.ac.uk/pdbsum/8bur PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bur ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.

Design principles for cyclin K molecular glue degraders.,Kozicka Z, Suchyta DJ, Focht V, Kempf G, Petzold G, Jentzsch M, Zou C, Di Genua C, Donovan KA, Coomar S, Cigler M, Mayor-Ruiz C, Schmid-Burgk JL, Haussinger D, Winter GE, Fischer ES, Slabicki M, Gillingham D, Ebert BL, Thoma NH Nat Chem Biol. 2024 Jan;20(1):93-102. doi: 10.1038/s41589-023-01409-z. Epub 2023 , Sep 7. PMID:37679459<ref>PMID:37679459</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8bur" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Focht V]]
[[Category: Kempf G]]
[[Category: Kozicka Z]]
[[Category: Thoma NH]]