4KCX

BRDT in complex with Dinaciclib

Summary for 4KCX

• Entry DOI: 10.2210/pdb4kcx/pdb
• Descriptor: Bromodomain testis-specific protein, 3-[({3-ethyl-5-[(2S)-2-(2-hydroxyethyl)piperidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl}amino)methyl]-1-hydroxypyridinium, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: brdt, bromodomain containing protein testis specific, cell cycle-inhibitor complex, cell cycle/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q58F21
• Total number of polymer chains: 2
• Total formula weight: 28726.75

Authors

Martin, M.P.,Schonbrunn, E. (deposition date: 2013-04-24, release date: 2013-09-18, Last modification date: 2023-09-20)

Primary citation

Martin, M.P.,Olesen, S.H.,Georg, G.I.,Schonbrunn, E.
Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.
Acs Chem.Biol., 8:2360-2365, 2013

PubMed 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.

PubMed: 24007471
DOI: 10.1021/cb4003283

Experimental method

X-RAY DIFFRACTION (2 Å)