7VS0
crystal structure of BRD2-BD2 in complex with purine derivative
Summary for 7VS0
| Entry DOI | 10.2210/pdb7vs0/pdb |
| Descriptor | Bromodomain-containing protein 2, Doxofylline, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | bet family, bet inhibitor, bromodomain inhibitor, brd2-bd1 inhibitor, transcription, transcription-inhibitor complex, transcription/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 14149.07 |
| Authors | Padmanabhan, B.,Arole, A.,Deshmukh, P.,Ashok, S.,Mathur, S. (deposition date: 2021-10-25, release date: 2023-02-01, Last modification date: 2023-11-29) |
| Primary citation | Arole, A.H.,Deshmukh, P.,Sridhar, A.,Mathur, S.,Mahalingaswamy, M.,Subramanya, H.,Dalavaikodihalli Nanjaiah, N.,Padmanabhan, B. Structural and biochemical insights into purine-based drug molecules in hBRD2 delineate a unique binding mode opening new vistas in the design of inhibitors of the BET family. Acta Crystallogr D Struct Biol, 79:758-774, 2023 Cited by PubMed Abstract: The bromodomain and extra-terminal (BET) family proteins, which are involved in chromatin function, have been shown to be promising drug targets in several pathological conditions, including cancer and inflammation. There is considerable interest in the development of BET inhibitors with novel scaffolds to modulate the epigenesis of such diseases. Here, high-resolution crystal structures of the purine class of FDA-approved drugs (theophylline, doxophylline and acyclovir) and non-FDA-approved compounds (3-methyl-7-propylxanthine and theobromine) complexed with hBRD2 bromodomains BD1 and BD2 are reported. Remarkably, a new binding site is exhibited by stacking the compounds against the WPF shelf of BD1 and BD2. This serendipitous binding, in addition to the known acetyl-lysine binding site, sufficiently anchors the ligands in the solvent-exposed region. In addition, slight variations in the lipophilicity of these molecules significantly affected the in vitro binding affinity and selectivity towards BD1 compared with BD2. This idiosyncratic binding provides a new structural framework to link these sites for the development of next-generation inhibitors of the BET family. PubMed: 37432115DOI: 10.1107/S2059798323005211 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
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