Structural highlights
FunctionATAD2_HUMAN May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.[1] Publication Abstract from PubMedPreventing histone recognition by bromodomains emerges as an attractive therapeutic approach in cancer. Overexpression of ATAD2A in cancer cells is associated with poor prognosis making the bromodomain of ATAD2A a promising epigenetic therapeutic target. In the development of an in vitro assay and identification of small molecule ligands, we conducted structure-guided studies which revealed a conformationally flexible ATAD2A bromodomain. Structural studies on apo-, peptide and small molecule-ATAD2A complexes (by co-crystalization) revealed the bromodomain adopts a "closed", histone-compatible conformation, and a more "open" ligand-compatible conformation of the binding-site respectively. An unexpected conformational change of the conserved asparagine residue plays an important role in driving the peptide-binding conformation remodelling. We also identified dimethylisoxazole-containing ligands as ATAD2A binders which aided in the validation of the in vitro screen and in the analysis of these conformational studies. Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2A.,Poncet-Montange G, Zhan Y, Bardenhagen JP, Petrocchi A, Leo E, Shi X, Lee Iv GR, Leonard PG, Geck Do MK, Cardozo MG, Andersen JN, Palmer WS, Jones P, Ladbury JE Biochem J. 2014 Dec 8. PMID:25486442[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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