title: Histone recognition and large-scale structural analysis of the human bromodomain family.
abstract: Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK. panagis.filippakopoulos@sgc.ox.ac.uk
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Maria
authors.initials: M
authors.lastname: Mangos
authors.forename: Tracy
authors.initials: T
authors.lastname: Keates
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.forename: Ildiko
authors.initials: I
authors.lastname: Felletar
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D015894:Genome, Human; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000032:analysis
chemical_list: D006657:Histones; D020543:Proteome; D008239:Lysine