title: Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2.
abstract: Preventing histone recognition by bromodomains emerges as an attractive therapeutic approach in cancer. Overexpression of ATAD2 (ATPase family AAA domain-containing 2 isoform A) in cancer cells is associated with poor prognosis making the bromodomain of ATAD2 a promising epigenetic therapeutic target. In the development of an in vitro assay and identification of small molecule ligands, we conducted structure-guided studies which revealed a conformationally flexible ATAD2 bromodomain. Structural studies on apo-, peptide-and small molecule-ATAD2 complexes (by co-crystallization) revealed that the bromodomain adopts a 'closed', histone-compatible conformation and a more 'open' ligand-compatible conformation of the binding site respectively. An unexpected conformational change of the conserved asparagine residue plays an important role in driving the peptide-binding conformation remodelling. We also identified dimethylisoxazole-containing ligands as ATAD2 binders which aided in the validation of the in vitro screen and in the analysis of these conformational studies.
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Poncet-Montange
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Yanai
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Bardenhagen
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Leo
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.affiliation: †Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston TX 77030, U.S.A.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Lee
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Leonard
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Geck Do
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Mario G
authors.initials: MG
authors.lastname: Cardozo
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Jannik N
authors.initials: JN
authors.lastname: Andersen
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Wylie S
authors.initials: WS
authors.lastname: Palmer
authors.affiliation: *Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Unit 1954, 1515 Holcombe Blvd, Houston, TX 77030, U.S.A.
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.affiliation: †Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston TX 77030, U.S.A.
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D019921:Biotinylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006657:Histones / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D018583:Pliability; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062368:meta-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006657:Histones; D007555:Isoxazoles; D008024:Ligands; D050505:Mutant Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013449:Sulfonamides; D062368:meta-Aminobenzoates; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities