Structural basis for CaVα2δ:gabapentin binding

Gabapentinoid drugs for pain and anxiety act on the CaV2{delta}-1 and CaV2{delta}-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/CaV{beta}3/CaV2{delta}-1 channel. The data reveal a binding pocket in the CaV2{delta}-1 dCache1 domain that completely encapsulates gabapentin and define CaV2{delta} isoform sequence variations that explain gabapentin binding selectivity of CaV2{delta}-1 and CaV2{delta}-2.