7vds: Difference between revisions
New page: '''Unreleased structure''' The entry 7vds is ON HOLD until Paper Publication Authors: Malojcic, G., Clugston, S.L., Daniels, M., Harmange, J.C., Ledeborer, M. Description: The structur... |
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The | ==The structure of cyclin-dependent kinase 5 (CDK5) in complex with p25 and Compound 24== | ||
<StructureSection load='7vds' size='340' side='right'caption='[[7vds]], [[Resolution|resolution]] 3.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7vds]] 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=7VDS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VDS 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]] 3.05Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=61U:5-fluoranyl-4-[[2-[(1R)-1-(1-methylpiperidin-4-yl)-1-oxidanyl-ethyl]-1,6-naphthyridin-7-yl]amino]-2-morpholin-4-yl-benzenecarbonitrile'>61U</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7vds FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vds OCA], [https://pdbe.org/7vds PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vds RCSB], [https://www.ebi.ac.uk/pdbsum/7vds PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vds ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CD5R1_HUMAN CD5R1_HUMAN] p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic human disease, but to date, only one therapy (tolvaptan) is approved to treat kidney cysts in ADPKD patients. Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinase family, has been implicated as a target for treating ADPKD. However, no compounds have been disclosed to date that selectively inhibit CDK5 while sparing the broader CDK family members. Herein, we report the discovery of CDK5 inhibitors, including GFB-12811, that are highly selective over the other tested kinases. In cellular assays, our compounds demonstrate CDK5 target engagement while avoiding anti-proliferative effects associated with inhibiting other CDKs. In addition, we show that the compounds in this series exhibit promising in vivo PK profiles, enabling their use as tool compounds for interrogating the role of CDK5 in ADPKD and other diseases. | |||
Discovery and Optimization of Highly Selective Inhibitors of CDK5.,Daniels MH, Malojcic G, Clugston SL, Williams B, Coeffet-Le Gal M, Pan-Zhou XR, Venkatachalan S, Harmange JC, Ledeboer M J Med Chem. 2022 Feb 24;65(4):3575-3596. doi: 10.1021/acs.jmedchem.1c02069. Epub , 2022 Feb 10. PMID:35143203<ref>PMID:35143203</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7vds" style="background-color:#fffaf0;"></div> | ||
[[Category: Clugston | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: Ledeborer | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Clugston SL]] | |||
[[Category: Daniels M]] | |||
[[Category: Harmange JC]] | |||
[[Category: Ledeborer M]] | |||
[[Category: Malojcic G]] | |||