Structural basis for Ca V α 2 δ:gabapentin binding.

Gabapentinoid drugs for pain and anxiety act on the Ca V α 2 δ-1 and Ca V α 2 δ-2 subunits of high-voltage-activated calcium channels (Ca V 1s and Ca V 2s). Here we present the cryo-EM structure of the gabapentin-bound brain and cardiac Ca V 1.2/Ca V β 3 /Ca V α 2 δ-1 channel. The data reveal a binding pocket in the Ca V α 2 δ-1 dCache1 domain that completely encapsulates gabapentin and define Ca V α 2 δ isoform sequence variations that explain the gabapentin binding selectivity of Ca V α 2 δ-1 and Ca V α 2 δ-2.