Binding Motifs in the CBP Bromodomain: An Analysis of 20 Crystal Structures of Complexes with Small Molecules

We
analyze 20 crystal structures of complexes between the CBP bromodomain
and small-molecule ligands that belong to eight different chemotypes
identified by docking. The binding motif of the moiety that mimics
the natural ligand (acetylated side chain of lysine) at the bottom
of the binding pocket is conserved. In stark contrast, the rest of
the ligands form different interactions with different side chains
and backbone polar groups on the outer rim of the binding pocket.
Hydrogen bonds are direct or water-bridged. van der Waals contacts
are optimized by rotations of hydrophobic side chains and a slight
inward displacement of the ZA loop. Rare types of interactions are
observed for some of the ligands.