title: Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain.
abstract: Bromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ HAT complex and contains a unique combination of domains typically found in chromatin-associated factors, which include plant homeodomain (PHD) fingers, a bromodomain and a proline-tryptophan-tryptophan-proline (PWWP) domain. Bromodomains are conserved structural motifs generally known to recognize acetylated histones, and the BRPF1 bromodomain preferentially selects for H2AK5ac, H4K12ac and H3K14ac. We solved the X-ray crystal structures of the BRPF1 bromodomain in complex with the H2AK5ac and H4K12ac histone peptides. Site-directed mutagenesis on residues in the BRPF1 bromodomain-binding pocket was carried out to investigate the contribution of specific amino acids on ligand binding. Our results provide critical insights into the molecular mechanism of ligand binding by the BRPF1 bromodomain, and reveal that ordered water molecules are an essential component driving ligand recognition.
authors.affiliation: Department of Pharmaceutical Science, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors.forename: Mulu Y
authors.initials: MY
authors.lastname: Lubula
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Eckenroth
authors.affiliation: Department of Pharmaceutical Science, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Carlson
authors.affiliation: Department of Pharmaceutical Science, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Poplawski
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Maksymilian
authors.initials: M
authors.lastname: Chruszcz
authors.affiliation: Department of Pharmaceutical Science, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA. Electronic address: karen.glass@acphs.edu.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Glass
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D006657:Histones; D008024:Ligands; D008239:Lysine; D009687:Nuclear Proteins; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Bromodomain-PHD finger protein 1; Circular dichroism; Epigenetics; Isothermal titration calorimetry; Site-directed mutagenesis; X-ray crystallography