Cyclic nucleotide-gated (CNG) channels are activated in response to the direct binding of cyclic nucleotides to an intracellular domain. This domain is thought to contain a β roll and two α helices, designated the B and C helices. To probe the conformational changes occurring in the ligand-binding domain during channel activation, we used the substituted cysteine accessibility method (SCAM). We found that a residue in the roll, C505, is more accessible in unliganded channels than in liganded channels, whereas a residue in the C helix, G597C, is more accessible in closed channels than in open channels. These results support a molecular mechanism for channel activation in which the ligand initially binds to the β roll, followed by an opening allosteric transition involving the relative movement of the C helix toward the β roll.
Matulef, K., Flynn, G. E., & Zagotta, W. N. (1999). Molecular rearrangements in the ligand-binding domain of cyclic nucleotide-gated channels. Neuron, 24(2), 443–452. https://doi.org/10.1016/S0896-6273(00)80857-0