Conformational landscape of cGMP activation of the human cone photoreceptor CNG channel

Cyclic nucleotide-gated (CNG) channels transduce chemical signals into electrical signals in sensory receptors and neurons and are essential for vision and smell. Although they are members of the voltage-gated ion channel superfamily, CNG channels are insensitive to membrane potential and are instead activated by intracellular cGMP or cAMP. To better understand how CNG channels work as molecular machines, we have determined high-resolution structures of cGMP-activated eukaryotic (nematode and human) CNG channels in various conditions and states. I will briefly display these structures and illustrate how they provide unprecedented mechanistic insights into CNG channel properties and mechanisms. I will in particular showcase and dissect the structures of the cGMP-activated human cone photoreceptor CNG channel, which is composed of CNGA3 and CNGB3 subunits. We have captured this channel in closed, transition, pre-open and open states in detergent or lipid nanodisc, all with fully bound cGMP. The pre-open and open states are obtained only in the lipid nanodisc, suggesting a critical role of lipids in tuning the energetic landscape of CNGA3/CNGB3 activation. The different states exhibit subunit-unique, incremental and distinct conformational rearrangements that originate in the cyclic nucleotide-binding domain (which is 50-60 Å away from the activation gate located in the central cavity), propagate through the coupling C-linker/gating ring to the transmembrane domain, and gradually open the cavity gate in S6. Our study illustrates a spatial conformational-change wave of allosteric gating of a vertebrate CNG channel by its natural ligand and provides an expanded framework for studying CNG functions and channelopathy.