PDBsum entry 4kcx

Cell cycle/inhibitor

PDB id: 4kcx

Contents

Protein chains

106 a.a.

Ligands

1QK ×2

Metals

_CL

Waters ×137

References listed in PDB file

Key reference

• Title: Cyclin-Dependent kinase inhibitor dinaciclib interacts with the acetyl-Lysine recognition site of bromodomains.
• Authors: M.P.Martin, S.H.Olesen, G.I.Georg, E.Schönbrunn.
• Ref.: Acs Chem Biol, 2013, 8, 2360-2365. [DOI no: 10.1021/cb4003283]
• PubMed id: 24007471

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.