4XY9

Crystal Structure of the first bromodomain of human BRD4 in complex with a 2-amine-9H-purine ligand

Summary for 4XY9

• Entry DOI: 10.2210/pdb4xy9/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 6-(5-bromo-2-methoxyphenyl)-9H-purin-2-amine, ... (4 entities in total)
• Functional Keywords: bromodomain, complex, ligand, structural genomics consortium, sgc, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15481.59

Authors

Picaud, S.,von Delft, F.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Filippakopoulos, P.,Structural Genomics Consortium (SGC) (deposition date: 2015-02-02, release date: 2015-03-11, Last modification date: 2024-05-08)

Primary citation

Picaud, S.,Strocchia, M.,Terracciano, S.,Lauro, G.,Mendez, J.,Daniels, D.L.,Riccio, R.,Bifulco, G.,Bruno, I.,Filippakopoulos, P.
9H-Purine Scaffold Reveals Induced-Fit Pocket Plasticity of the BRD9 Bromodomain.
J.Med.Chem., 58:2718-2736, 2015

PubMed Abstract: The 2-amine-9H-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 11 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-9H-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.

PubMed: 25703523
DOI: 10.1021/jm501893k

Experimental method

X-RAY DIFFRACTION (1.83 Å)