Figure 2.

Gabapentinoid and amino acid–binding pockets of α₂δ-1 – α₂δ-4. Phe221/Phe256 (F221/F256) creates steric hindrance in the ligand-binding pocket of α₂δ-3 and α₂δ-4 proteins. Superimposed structures of α₂δ-1 and α₂δ-2 (a) and α₂δ-3 and α₂δ-4 (b) ligand-binding pockets. α₂δ-1 is the rabbit protein cryo-EM structure, α₂δ-2 to α₂δ-4 are the AlphaFold models. Gabapentin is docked to the binding pocket of α₂δ-1. Each of α₂δ-2 to α₂δ-4 was superimposed on α₂δ1; α₂δ-3 and α₂δ-4 then were extracted and placed on panel B for clarity. A figure with all the proteins simultaneously superimposed on α₂δ-1 can be found on GitHub at the following link https://github.com/ToshkaDev/Alpha2Delta-proteins-review. In pink font the first two residues of the RRR (in α₂δ-1 and α₂δ-2)/RNR (in α₂δ-3 and α₂δ-4) sequence are shown – as can be seen they are not involved in ligand binding. Other residues, except for the residue corresponding to Asp454 (D454) in α₂δ-1, denote the amino acid–binding motif .[35]