View source for 8b54


==CDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibitor LGR6768==
<StructureSection load='8b54' size='340' side='right'caption='[[8b54]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8b54]] is a 4 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=8B54 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B54 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=P2V:~{N}-[(2-phenylphenyl)methyl]-5-piperidin-4-ylsulfanyl-3-propan-2-yl-2~{H}-pyrazolo[4,3-d]pyrimidin-7-amine'>P2V</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=8b54 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b54 OCA], [https://pdbe.org/8b54 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b54 RCSB], [https://www.ebi.ac.uk/pdbsum/8b54 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b54 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 A resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors.

Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7.,Kovalova M, Havlicek L, Djukic S, Skerlova J, Perina M, Pospisil T, Reznickova E, Rezacova P, Jorda R, Krystof V Biomed Pharmacother. 2023 Mar 15;161:114492. doi: 10.1016/j.biopha.2023.114492. PMID:36931035<ref>PMID:36931035</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8b54" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Djukic S]]
[[Category: Rezacova P]]
[[Category: Skerlova J]]