4bcq: Difference between revisions
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==Structure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor== | |||
<StructureSection load='4bcq' size='340' side='right'caption='[[4bcq]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bcq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BCQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BCQ 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]] 2.4Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TJF:4-[4-METHYL-2-(METHYLAMINO)-1,3-THIAZOL-5-YL]-2-{[3-(MORPHOLIN-4-YLCARBONYL)PHENYL]AMINO}PYRIMIDINE-5-CARBONITRILE'>TJF</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=4bcq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bcq OCA], [https://pdbe.org/4bcq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bcq RCSB], [https://www.ebi.ac.uk/pdbsum/4bcq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bcq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CCNA2_BOVIN CCNA2_BOVIN] Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalise the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimida- zone-1-beta-D-ribofuranoside (DRB). Finally, based on 11 co-crystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site, rather than from the formation of specific polar contacts. | |||
Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.,Hole A, Baumli S, Shao H, Shi S, Pepper C, Fischer PM, Wang S, Endicott JA, Noble M J Med Chem. 2012 Dec 20. PMID:23252711<ref>PMID:23252711</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4bcq" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cyclin 3D structures|Cyclin 3D structures]] | |||
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Baumli S]] | |||
[[Category: Endicott JA]] | |||
[[Category: Hole AJ]] | |||
[[Category: Noble MEM]] | |||
[[Category: Wang S]] | |||
Latest revision as of 11:20, 23 October 2024
Structure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitorStructure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor
Structural highlights
FunctionCCNA2_BOVIN Essential for the control of the cell cycle at the G1/S (start) and the G2/M (mitosis) transitions. Publication Abstract from PubMedCyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalise the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimida- zone-1-beta-D-ribofuranoside (DRB). Finally, based on 11 co-crystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site, rather than from the formation of specific polar contacts. Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.,Hole A, Baumli S, Shao H, Shi S, Pepper C, Fischer PM, Wang S, Endicott JA, Noble M J Med Chem. 2012 Dec 20. PMID:23252711[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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