Open AccessStructural Insights into the Recognition of Mono- and Diacetylated Histones by the ATAD2B Bromodomain
Author(s) -
Jonathan T. Lloyd,
Kyle McLaughlin,
Mulu Y. Lubula,
Andrea Dest,
Cong Gao,
Margaret Phillips,
Marco Tonelli,
Gabriel Cornilescu,
Matthew R. Marunde,
Chiara M. Evans,
Samuel P. Boyson,
Samuel Carlson,
MichaelChristopher Keogh,
John L. Markley,
Seth Frietze,
Karen C. Glass
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01178
Subject(s) - bromodomain , chemistry , histone , brd4 , chromatin , function (biology) , computational biology , biochemistry , mechanism (biology) , plasma protein binding , microbiology and biotechnology , dna , biology , philosophy , epistemology
Bromodomains exhibit preferences for specific patterns of post-translational modifications on core and variant histone proteins. We examined the ligand specificity of the ATAD2B bromodomain and compared it to its closely related paralogue in ATAD2. We show that the ATAD2B bromodomain recognizes mono- and diacetyllysine modifications on histones H4 and H2A. A structure-function approach was used to identify key residues in the acetyllysine-binding pocket that dictate the molecular recognition process, and we examined the binding of an ATAD2 bromodomain inhibitor by ATAD2B. Our analysis demonstrated that critical contacts required for bromodomain inhibitor coordination are conserved between the ATAD2/B bromodomains, with many residues playing a dual role in acetyllysine recognition. We further characterized an alternative splice variant of ATAD2B that results in a loss of function. Our results outline the structural and functional features of the ATAD2B bromodomain and identify a novel mechanism regulating the interaction of the ATAD2B protein with chromatin.