View source for 8p81


==Crystal structure of human Cdk12/Cyclin K in complex with inhibitor SR-4835==
<StructureSection load='8p81' size='340' side='right'caption='[[8p81]], [[Resolution|resolution]] 2.68&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8p81]] is a 2 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=8P81 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8P81 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]] 2.68&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RMF:~{N}-[[5,6-bis(chloranyl)-1~{H}-benzimidazol-2-yl]methyl]-9-(1-methylpyrazol-4-yl)-2-morpholin-4-yl-purin-6-amine'>RMF</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=8p81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8p81 OCA], [https://pdbe.org/8p81 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8p81 RCSB], [https://www.ebi.ac.uk/pdbsum/8p81 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8p81 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibition of cyclin-dependent kinases (CDKs) has evolved as an emerging anticancer strategy. In addition to the cell cycle-regulating CDKs, the transcriptional kinases Cdk12 and Cdk13 have become the focus of interest as they mediate a variety of functions, including the transition from transcription initiation to elongation and termination, precursor mRNA splicing, and intronic polyadenylation. Here, we determine the crystal structure of the small molecular inhibitor SR-4835 bound to the Cdk12/cyclin K complex at 2.68 A resolution. The compound's benzimidazole moiety is embedded in a unique hydrogen bond network mediated by the kinase hinge region with flanking hydroxy groups of the Y815 and D819 side chains. Whereas the SR-4835 head group targets the adenine-binding pocket, the kinase's glycine-rich loop is shifted down toward the activation loop. Additionally, the alphaC-helix adopts an inward conformation, and the phosphorylated T-loop threonine interacts with all three canonical arginines, a hallmark of CDK activation that is altered in Cdk12 and Cdk13. Dose-response inhibition measurements with recombinant CMGC kinases show that SR-4835 is highly specific for Cdk12 and Cdk13 following a 10-fold lower potency for Cdk10. Whereas other CDK-targeting compounds exhibit tighter binding affinities and higher potencies for kinase inhibition, SR-4835 can be considered a selective transcription elongation antagonist. Our results provide the basis for a rational improvement of SR-4835 toward Cdk12 inhibition and a gain in selectivity over other transcription regulating CDKs.

The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation.,Schmitz M, Kaltheuner IH, Anand K, Duster R, Moecking J, Monastyrskyi A, Duckett DR, Roush WR, Geyer M J Biol Chem. 2024 Jan;300(1):105501. doi: 10.1016/j.jbc.2023.105501. Epub 2023 , Nov 26. PMID:38016516<ref>PMID:38016516</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 8p81" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Anand K]]
[[Category: Geyer M]]
[[Category: Schmitz M]]