Structure of the human cone photoreceptor cyclic nucleotide-gated channel

A cryo-EM structure of the human cone photoreceptor CNG channel reveals an odd subunit stoichiometry and unique structural features conferred by a distinct subunit, providing a framework to study cone CNG channel physiology and channelopathies. Cyclic nucleotide-gated (CNG) channels transduce light-induced chemical signals into electrical signals in retinal cone and rod photoreceptors. Structures of native CNG channels, which are heterotetramers formed by CNGA and CNGB subunits, have not been obtained. In the present study, we report a high-resolution cryo-electron microscopy structure of the human cone CNG channel in the apo closed state. The channel contains three CNGA3 and one CNGB3 subunits. Arg403 in the pore helix of CNGB3 projects into an asymmetric selectivity filter and forms hydrogen bonds with two pore-lining backbone carbonyl oxygens. Arg442 in S6 of CNGB3 protrudes into and occludes the pore below the hydrophobic cavity gate previously observed in homotetrameric CNGA channels. It is interesting that Arg403Gln is a disease mutation, and Arg442 is replaced by glutamine in some animal species with dichromatic or monochromatic vision. These and other unique structural features and the disease link conferred by CNGB3 indicate a critical role of CNGB3 in shaping cone photoresponses.

Automated summary

The cryo-EM structure of the human cone photoreceptor CNG channel reveals an unusual subunit stoichiometry and unique structural features due to a distinct subunit, contributing to the understanding of cone CNG channel physiology and channelopathies. This study provides insight into the critical role of CNGB3 in shaping cone photoresponses, highlighting the importance of its structural features and disease mutations in determining visual function.