PDBsum entry 4bch

Transferase/cell cycle

PDB id: 4bch

Contents

Protein chains

309 a.a.

252 a.a.

Ligands

T7Z

GOL ×2

Waters ×13

PDB id:

4bch

Name:

Transferase/cell cycle

Title:

Structure of cdk9 in complex with cyclin t and a 2-amino-4-heteroaryl- pyrimidine inhibitor

Structure:

Cyclin-dependent kinase 9. Chain: a. Fragment: residues 2-330. Synonym: c-2k, cell division cycle 2-like protein kinase 4, cell division protein kinase 9, serine/threonine-protein kinase pitalre, tat-associated kinase complex catalytic subunit. Engineered: yes. Cyclin-t1. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Resolution:

2.96Å R-factor: 0.169 R-free: 0.210

Authors:

A.J.Hole,S.Baumli,S.Wang,J.A.Endicott,M.E.M.Noble

Key ref:

A.J.Hole et al. (2013). Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. J Med Chem, 56, 660-670. PubMed id: 23252711

Date:

02-Oct-12 Release date: 09-Jan-13

Protein chain

P50750  (CDK9_HUMAN) -  Cyclin-dependent kinase 9 from Homo sapiens

Seq: 372 a.a.

Struc: 309 a.a.*

Protein chain

O60563  (CCNT1_HUMAN) -  Cyclin-T1 from Homo sapiens

Seq: 726 a.a.

Struc: 252 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 3: Chain A: E.C.2.7.11.23 - [RNA-polymerase]-subunit kinase.
• Reaction: [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 56:660-670 (2013)

PubMed id: 23252711

Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.

A.J.Hole, S.Baumli, H.Shao, S.Shi, S.Huang, C.Pepper, P.M.Fischer, S.Wang, J.A.Endicott, M.E.Noble.

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-β-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.