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 the gabapentin binding selectivity of CaVα2δ-1 and CaVα2δ-2. Gabapentinoid drugs are widely used for pain, epilepsy and mental disorders. Chen et al. report the structure of a gabapentin-bound brain and heart calcium channel, revealing the gabapentin binding site and isoform-selective binding determinants.