View source for 6td3


==Structure of DDB1 bound to CR8-engaged CDK12-cyclinK==
<StructureSection load='6td3' size='340' side='right'caption='[[6td3]], [[Resolution|resolution]] 3.46&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TD3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TD3 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]] 3.46&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RC8:(2R)-2-({9-(1-METHYLETHYL)-6-[(4-PYRIDIN-2-YLBENZYL)AMINO]-9H-PURIN-2-YL}AMINO)BUTAN-1-OL'>RC8</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=6td3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6td3 OCA], [https://pdbe.org/6td3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6td3 RCSB], [https://www.ebi.ac.uk/pdbsum/6td3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6td3 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation(1). Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets(2). They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines(3-5), we identify CR8-a cyclin-dependent kinase (CDK) inhibitor(6)-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.

The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K.,Slabicki M, Kozicka Z, Petzold G, Li YD, Manojkumar M, Bunker RD, Donovan KA, Sievers QL, Koeppel J, Suchyta D, Sperling AS, Fink EC, Gasser JA, Wang LR, Corsello SM, Sellar RS, Jan M, Gillingham D, Scholl C, Frohling S, Golub TR, Fischer ES, Thoma NH, Ebert BL Nature. 2020 Jun 3. pii: 10.1038/s41586-020-2374-x. doi:, 10.1038/s41586-020-2374-x. PMID:32494016<ref>PMID:32494016</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6td3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Cyclin 3D structures|Cyclin 3D structures]]
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
*[[DNA damage-binding protein|DNA damage-binding protein]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Bunker RD]]
[[Category: Kozicka Z]]
[[Category: Petzold G]]
[[Category: Thoma NH]]