9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain
The 2-amine-9<em>H</em>-purine scaffold was identified as a weak bromodomain template and was developed via iterative structure based design into a potent nanomolar ligand for the bromodomain of human BRD9 with small residual micromolar affinity toward the bromodomain of BRD4. Binding of...
| Principais autores: | , , , , , , , , , |
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| Formato: | Journal article |
| Idioma: | English |
| Publicado em: |
American Chemical Society
2015
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| _version_ | 1826269357870678016 |
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| author | Picaud, S Strocchia, M Terracciano, S Lauro, G Mendez, J Daniels, D Riccio, R Bifulco, G Bruno, I Filippakopoulos, P |
| author_facet | Picaud, S Strocchia, M Terracciano, S Lauro, G Mendez, J Daniels, D Riccio, R Bifulco, G Bruno, I Filippakopoulos, P |
| author_sort | Picaud, S |
| collection | OXFORD |
| description | The 2-amine-9<em>H</em>-purine scaffold was identified as a weak bromodomain template and was developed via iterative structure based design into a potent nanomolar ligand for the bromodomain of human BRD9 with small residual micromolar affinity toward the bromodomain of BRD4. Binding of the lead compound <strong>11</strong> to the bromodomain of BRD9 results in an unprecedented rearrangement of residues forming the acetyllysine recognition site, affecting plasticity of the protein in an induced-fit pocket. The compound does not exhibit any cytotoxic effect in HEK293 cells and displaces the BRD9 bromodomain from chromatin in bioluminescence proximity assays without affecting the BRD4/histone complex. The 2-amine-9<em>H</em>-purine scaffold represents a novel template that can be further modified to yield highly potent and selective tool compounds to interrogate the biological role of BRD9 in diverse cellular systems. |
| first_indexed | 2024-03-06T21:23:48Z |
| format | Journal article |
| id | oxford-uuid:42669dfb-2eea-4f14-b98c-6e2055ad7209 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:23:48Z |
| publishDate | 2015 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:42669dfb-2eea-4f14-b98c-6e2055ad72092022-03-26T14:49:15Z9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomainJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:42669dfb-2eea-4f14-b98c-6e2055ad7209EnglishORA DepositAmerican Chemical Society2015Picaud, SStrocchia, MTerracciano, SLauro, GMendez, JDaniels, DRiccio, RBifulco, GBruno, IFilippakopoulos, PThe 2-amine-9<em>H</em>-purine scaffold was identified as a weak bromodomain template and was developed via iterative structure based design into a potent nanomolar ligand for the bromodomain of human BRD9 with small residual micromolar affinity toward the bromodomain of BRD4. Binding of the lead compound <strong>11</strong> to the bromodomain of BRD9 results in an unprecedented rearrangement of residues forming the acetyllysine recognition site, affecting plasticity of the protein in an induced-fit pocket. The compound does not exhibit any cytotoxic effect in HEK293 cells and displaces the BRD9 bromodomain from chromatin in bioluminescence proximity assays without affecting the BRD4/histone complex. The 2-amine-9<em>H</em>-purine scaffold represents a novel template that can be further modified to yield highly potent and selective tool compounds to interrogate the biological role of BRD9 in diverse cellular systems. |
| spellingShingle | Picaud, S Strocchia, M Terracciano, S Lauro, G Mendez, J Daniels, D Riccio, R Bifulco, G Bruno, I Filippakopoulos, P 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain |
| title | 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain |
| title_full | 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain |
| title_fullStr | 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain |
| title_full_unstemmed | 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain |
| title_short | 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain |
| title_sort | 9h purine scaffold reveals induced fit pocket plasticity of the brd9 bromodomain |
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