Mechanism of ligand activation of cyclic nucleotide-gated channels revealed
Yang Lab, Frank Lab
Cyclic nucleotide-gated (CNG) channels are essential for vision and smell in vertebrates. These channels convert electromagnetic and chemical signals into electrical signals in the eye and nose, which are transmitted to and processed by the brain. Numerous hereditary mutations in CNG channel genes have been associated with degenerative visual disorders that cause blindness or color blindness. CNG channels conduct cations such as Na+, K+ and Ca2+, and are activated by intracellular cyclic nucleotides, cAMP and cGMP. Despite extensive research, the molecular mechanisms of how cyclic nucleotides open CNG channels remain unclear.
The Yang lab, Frank lab and their collaborators have solved atomic-resolution (2.6 and 2.7 Å, respectively) three-dimensional structures of TAX-4, a nematode CNG channel, in both the cGMP-free closed state and cGMP-bound open state. Structural comparisons reveal global and complex conformational changes underlying the opening and closing of the channel, from the cyclic nucleotide-binding domain to the activation gate located ~51-54 Å away in the S6 transmembrane segment. The structures also challenge a long-held posit in the ion channel field regarding the activation gate of CNG channels. This gate is widely believed to be formed by the selectivity filter, which confers the channels’ preference for cations. The structures show, however, that the selectivity filter does not undergo conformational changes upon cGMP binding and unbinding; instead, cGMP opens a hydrophobic gate formed by F403 and V407 located in the central cavity, a pore region in the middle of the cell membrane. In the closed state, the side-chains of F403 and V407 project to the center of the pore, prohibiting cation permeation; in the open state, the side-chains swing away from the pore axis, allowing cation permeation. These structures provide a framework for further studies on CNG channel properties, functions and channelopathies.
Reference: Mechanism of ligand activation of a eukaryotic cyclic nucleotide-gated channel