title: The "Gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains.
abstract: Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ∼200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Unzue
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Graziano
authors.initials: G
authors.lastname: Lolli
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Zechner
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Dolbois
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
authors.affiliation: Department of Chemistry and ‡Department of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nevado
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism; D007212:Indolizines / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D062105:Molecular Docking Simulation; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism*; D035165:Transcription Factors, General; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D007211:Indoles; D007212:Indolizines; D008024:Ligands; D008239:Lysine; D009687:Nuclear Proteins; D011506:Proteins; D054852:Small Molecule Libraries; D035165:Transcription Factors, General; C000609272:BAZ2B protein, human; D000092468:Bromodomain Containing Proteins; C086011:BRPF1 protein, human; C035094:indolizine; C494363:CREBBP protein, human