Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2
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 targe...
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| Veröffentlicht in: | Biochemical journal 2015-03, Vol.466 (2), p.337-346 |
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| creator | Poncet-Montange, Guillaume Zhan, Yanai Bardenhagen, Jennifer P Petrocchi, Alessia Leo, Elisabetta Shi, Xi Lee, 4th, Gilbert R Leonard, Paul G Geck Do, Mary K Cardozo, Mario G Andersen, Jannik N Palmer, Wylie S Jones, Philip Ladbury, John E |
| description | 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. |
| doi_str_mv | 10.1042/BJ20140933 |
| format | Article |
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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. 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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.</description><subject>Adenosine Triphosphatases - antagonists & inhibitors</subject><subject>Adenosine Triphosphatases - chemistry</subject><subject>Adenosine Triphosphatases - genetics</subject><subject>Adenosine Triphosphatases - metabolism</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>ATPases Associated with Diverse Cellular Activities</subject><subject>Binding Sites</subject><subject>Biotinylation</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - chemistry</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Histones - antagonists & inhibitors</subject><subject>Histones - chemistry</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Isoxazoles - chemical synthesis</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazoles - pharmacology</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>meta-Aminobenzoates - chemical synthesis</subject><subject>meta-Aminobenzoates - chemistry</subject><subject>meta-Aminobenzoates - pharmacology</subject><subject>Mutant Proteins - antagonists & inhibitors</subject><subject>Mutant Proteins - chemistry</subject><subject>Mutant Proteins - metabolism</subject><subject>Peptide Fragments - antagonists & inhibitors</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - metabolism</subject><subject>Pliability</subject><subject>Protein Conformation</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Protein Processing, Post-Translational</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Sulfonamides - chemical synthesis</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><issn>0264-6021</issn><issn>1470-8728</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtLAzEUhYMotlY3_gDJUoTRvOa1rPVNwY2uh5uZG40kzZhMRf-9I626OnD4-OAcQo45O-dMiYvLB8G4YrWUO2TKVcmyqhTVLpkyUaisYIJPyEFKb-yHUmyfTESuqkIpMSX-USeMH9hRHYMPXfBgV9Q4_LTaOjt80YgfCC7RV5uGsELaYz_YDjMKq44mD85RHxy2a4fU2ZexzdrgexisHhsTok80GDp_ml-JQ7JnRhcebXNGnm-unxZ32fLx9n4xX2atFHLI6rKGUgFWqlNCYZfrgqMG3Roo0IxjOy04wDg5z8tCC1GpHExR1y0YACnljJxuvH0M72tMQ-NtatE5WGFYp4YXeSlFLlU1omcbtI0hpYim6aP1EL8azpqfe5v_e0f4ZOtda4_dH_r7p_wGesd2Dg</recordid><startdate>20150301</startdate><enddate>20150301</enddate><creator>Poncet-Montange, Guillaume</creator><creator>Zhan, Yanai</creator><creator>Bardenhagen, Jennifer P</creator><creator>Petrocchi, Alessia</creator><creator>Leo, Elisabetta</creator><creator>Shi, Xi</creator><creator>Lee, 4th, Gilbert R</creator><creator>Leonard, Paul G</creator><creator>Geck Do, Mary K</creator><creator>Cardozo, Mario G</creator><creator>Andersen, Jannik N</creator><creator>Palmer, Wylie S</creator><creator>Jones, Philip</creator><creator>Ladbury, John E</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150301</creationdate><title>Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2</title><author>Poncet-Montange, Guillaume ; 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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. 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| ispartof | Biochemical journal, 2015-03, Vol.466 (2), p.337-346 |
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| subjects | Adenosine Triphosphatases - antagonists & inhibitors Adenosine Triphosphatases - chemistry Adenosine Triphosphatases - genetics Adenosine Triphosphatases - metabolism Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology ATPases Associated with Diverse Cellular Activities Binding Sites Biotinylation DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Histones - antagonists & inhibitors Histones - chemistry Histones - metabolism Humans Isoxazoles - chemical synthesis Isoxazoles - chemistry Isoxazoles - pharmacology Kinetics Ligands meta-Aminobenzoates - chemical synthesis meta-Aminobenzoates - chemistry meta-Aminobenzoates - pharmacology Mutant Proteins - antagonists & inhibitors Mutant Proteins - chemistry Mutant Proteins - metabolism Peptide Fragments - antagonists & inhibitors Peptide Fragments - chemistry Peptide Fragments - metabolism Pliability Protein Conformation Protein Interaction Domains and Motifs Protein Processing, Post-Translational Recombinant Proteins - chemistry Recombinant Proteins - metabolism Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology |
| title | Observed bromodomain flexibility reveals histone peptide- and small molecule ligand-compatible forms of ATAD2 |
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