Twenty Crystal Structures of Bromodomain and PHD Finger Containing Protein 1 (BRPF1)/Ligand Complexes Reveal Conserved Binding Motifs and Rare Interactions

BRPF1
plays a scaffolding role in transcription. We report on fragment
screening by high-throughput docking to the BRPF1 bromodomain which
resulted in six chemotypes with very favorable ligand efficiency (0.45–0.50
kcal/mol per non-hydrogen atom). Twenty crystal structures of BRPF1/ligand
complexes show structural conservation in the acetyllysine binding
site, common binding motifs, and unusual interactions (e.g., the replacement
of a conserved water molecule). The structural information is useful
for the design of chemical probes.