Structural highlights
Function
BRDT_HUMAN Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis. Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time. In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA. Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids. Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin.[1] [2] [3]
Publication Abstract from PubMed
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 A 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 A 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.
Cyclin-Dependent Kinase Inhibitor Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains.,Martin MP, Olesen SH, Georg GI, Schonbrunn E ACS Chem Biol. 2013 Sep 10. PMID:24007471[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jones MH, Numata M, Shimane M. Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics. 1997 Nov 1;45(3):529-34. PMID:9367677 doi:S0888-7543(97)95000-X
- ↑ Zheng Y, Yuan W, Zhou Z, Xu M, Sha JH. Molecular cloning and expression of a novel alternative splice variant of BRDT gene. Int J Mol Med. 2005 Feb;15(2):315-21. PMID:15647849
- ↑ Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE. Small-Molecule Inhibition of BRDT for Male Contraception. Cell. 2012 Aug 17;150(4):673-684. PMID:22901802 doi:10.1016/j.cell.2012.06.045
- ↑ Martin MP, Olesen SH, Georg GI, Schonbrunn E. Cyclin-Dependent Kinase Inhibitor Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains. ACS Chem Biol. 2013 Sep 10. PMID:24007471 doi:10.1021/cb4003283
