4BCH: Structure Of Cdk9 In Complex With Cyclin T And A 2-amino-4- Heteroaryl-pyrimidine Inhibitor

Citation:
Abstract
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 rationalize 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-dichlorobenzimidazone-1-beta-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal 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.
PDB ID: 4BCHDownload
MMDB ID: 106513
PDB Deposition Date: 2012/10/2
Updated in MMDB: 2013/02
Experimental Method:
x-ray diffraction
Resolution: 2.96  Å
Source Organism:
Similar Structures:
Biological Unit for 4BCH: dimeric; determined by software (PISA)
Molecular Components in 4BCH
Label Count Molecule
Proteins (2 molecules)
1
Cyclin-dependent Kinase 9(Gene symbol: CDK9)
Molecule annotation
1
Cyclin-t1(Gene symbol: CCNT1)
Molecule annotation
Chemicals (3 molecules)
1
1
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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