Previous studies have shown kinase inhibitors that bind to this pocket.
Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein protein interaction interface with CDK2/Cyclin A substrate.
In the cGMP complex, hydrogen bonding between the 2-NH2 grofp of guanine and Thr317 ensures that cGMP is bound in the syn-conformation; however, cAMP lacks this NH2 group and binds to the pocket in both syn- and anti-conformations.
Moreover, for compound 1, the 7-OH group binds to the pocket C6 by hydrogen bond interaction with Glu 277, the 1-CO-group forms a hydrogen bond with Arg 152 and Arg 292 of pocket C1, and the 5-OH group binds to the pocket C4 by hydrogen bond interaction with Asp151 (Fig. 7).
In the structure of the oxidized forms of Etrx2, a detergent molecule (Cyclofos-3™) or a HED molecule is bound to this hydrophobic pocket, very likely mimicking the redox partner interaction.
This suggests that, while both pharmacophores are competitive inhibitors of NADH-binding, they bind to the pocket in different ways.
These compounds bound to the pocket with an affinity similar to locostatin; however, their side chains allowed for binding to different regions within the RKIP binding pocket.
SH3 domains are structurally conserved domains of ~60 amino acids that bind a consensus sequence of X1- P2-p3-x4- P5 where 1 and 4 are aliphatic amino acids, 2 and 5 are always proline, and together this sequence binds to the hydrophobic pocket of the SH3 domain.
If an L-aa was to bind in this pocket, it would have to do so in one of the three theoretically possible conformations shown in Figure 4.
Binding of primed substrates to this pocket is proposed to position them correctly in the catalytic groove for subsequent phosphorylation by GSK-3 and to stabilize the active conformation of the enzyme [ 35, 36, 38].
