PDBsum entry 4kcx

Cell cycle/inhibitor

PDB id: 4kcx

Contents

Protein chains

106 a.a.

Ligands

1QK ×2

Metals

_CL

Waters ×137

PDB id:

4kcx

Name:

Cell cycle/inhibitor

Title:

Brdt in complex with dinaciclib

Structure:

Bromodomain testis-specific protein. Chain: a, b. Fragment: first bromodomain, unp residues 21-137. Synonym: cancer/testis antigen 9, ct9, ring3-like protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: brdt. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.00Å R-factor: 0.211 R-free: 0.253

Authors:

M.P.Martin,E.Schonbrunn

Key ref:

M.P.Martin et al. (2013). Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. Acs Chem Biol, 8, 2360-2365. PubMed id: 24007471 DOI: 10.1021/cb4003283

Date:

24-Apr-13 Release date: 18-Sep-13

Protein chains

Q58F21  (BRDT_HUMAN) -  Bromodomain testis-specific protein from Homo sapiens

Seq: 947 a.a.

Struc: 106 a.a.

DOI no: 10.1021/cb4003283

Acs Chem Biol 8:2360-2365 (2013)

PubMed id: 24007471

Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.

M.P.Martin, S.H.Olesen, G.I.Georg, E.Schönbrunn.

ABSTRACT

Bromodomain-containing proteins are considered atypical kinases, but their potential to interact with kinase inhibitors is unknown. Dinaciclib is a potent inhibitor of cyclin-dependent kinases (CDKs), which recently advanced to Phase III clinical trials for the treatment of leukemia. We determined the crystal structure of dinaciclib in complex with CDK2 at 1.7 Å resolution, revealing an elaborate network of binding interactions in the ATP site, which explains the extraordinary potency and selectivity of this inhibitor. Remarkably, dinaciclib also interacted with the acetyl-lysine recognition site of the bromodomain testis-specific protein BRDT, a member of the BET family of bromodomains. The binding mode of dinaciclib to BRDT at 2.0 Å resolution suggests that general kinase inhibitors ("hinge binders") possess a previously unrecognized potential to act as protein-protein inhibitors of bromodomains. The findings may provide a new structural framework for the design of next-generation bromodomain inhibitors using the vast chemical space of kinase inhibitors.