Structural basis for CaVα2δ:gabapentin binding

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

Automated summary

Gabapentinoid drugs act on specific subunits of calcium channels and have been used for pain, epilepsy, and mental disorders. This study presents the structure of a gabapentin-bound calcium channel, revealing the binding site and selectivity of different isoforms. This provides insights into the mechanism of action of these drugs.