Structural basis for CaVα2δ:gabapentin binding

Gabapentinoid drugs for pain and anxiety act on the CaVα2δ-1 and CaVα2δ-2 subunits of high-voltage activated calcium channels (CaV1s and CaV2s). Here, we present the cryo-EM structure of the gabapentin-bound brain and cardiac CaV1.2/CaVβ3/CaVα2δ-1 channel. The data reveal a binding pocket in the CaVα2δ-1 dCache1 domain that completely encapsulates gabapentin and define CaVα2δ isoform sequence variations that explain gabapentin binding selectivity of CaVα2δ-1 and CaVα2δ-2.