8sdo
From Proteopedia
ATAD2 bromodomain in complex with "oncohistone" mutation H4S1CK5ac (res 1-15) ligand
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 PubMedThe ATPase family AAA(+) domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure-function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in the context of adjacent post-translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands impact the recognition of an adjacent acetyllysine residue. Our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2/B BRDs, resulting in distinct binding modes. Impact of Combinatorial Histone Modifications on Acetyllysine Recognition by the ATAD2 and ATAD2B Bromodomains.,Phillips M, Malone KL, Boyle BW, Montgomery C, Kressy IA, Joseph FM, Bright KM, Boyson SP, Chang S, Nix JC, Young NL, Jeffers V, Frietze S, Glass KC J Med Chem. 2024 May 23;67(10):8186-8200. doi: 10.1021/acs.jmedchem.4c00210. Epub , 2024 May 11. PMID:38733345[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|