Advances in ion channel structure

Nearly 45 years have elapsed between the first reports of high-resolution structures of hemoglobin and myoglobin and the recent breakthroughs in high-resolution structures of ion-selective channels. Now, in a mere five years, we suddenly have crystal structures of channel proteins from several distinct functional classes (and a Nobel Prize to Rod MacKinnon and Peter Agre). This marks a major turning point in ion channel research, providing striking insights into the molecular basis of electrical signaling. Before these breakthroughs, researchers of ion channels were deeply absorbed with the question of what these molecules look like. Now that we are starting to see some details, a new level of understanding of excitable membranes is emerging.The nine articles in this special issue devoted to ion channel structure provide accounts of how these high-resolution structures have answered some major questions about ion channels, and bring into focus what questions are still outstanding. The clearest advances have been in our understanding of ion permeation and selectivity. For both K+ channels (Jordan and Miloshevsky) and Cl− channels (Dutzler), binding sites for the permeable ions play major roles. A more complex picture appears when we turn to questions about the nature of gating, and the structural transitions of ion channels. Doyle discusses models of membrane-spanning α-helices, and how they can tilt, rotate and bend during the gating transitions of various channels. The structure of the nicotinic ACh receptor in one state still leaves us wondering about how binding is transduced to gating, and how the gating transitions actually take place. Lester et al. discuss these issues for nicotinic receptors, and Colquhoun and Sivilotti focus on glycine receptors. Glutamate receptors are discussed by Wolmuth and Sobolevsky, who explore the faint shadows of similarity with K+ channels. Ahern and Horn consider the starkly different views on how the voltage sensor of voltage-gated channels transduces changes in membrane potential into a channel gating transition. Sukharev investigates the unique ability of mechanosensitive channels to sense and transduce mechanical force rather than ligand binding or voltage. Finally, DeFelice discusses the structural relations between ion channels and transporters, and how this might translate into interesting mechanistic parallels.It is easy to expect structural information to transform research on molecular mechanisms from a guessing game into a mundane exercise in reductionism. However, Francis Crick has commented on the shock experienced by molecular biologists when they discovered that solving protein structures did not immediately render function and mechanism obvious (quotation from Fersht in the review by Colquhoun and Sivilotti). The beautiful snapshots with atomic positions specified and locked in space do not answer two basic questions. (i) They do not tell us what physical forces stabilize the observed structure. (ii) They do not tell us how the structures interconvert. Insight into mechanism generally derives from the pursuit of these two questions, and the structures provide an essential framework. The reviews on ion channel structure in this issue convey the excitement of this new work and suggest how this information can be used to forge ahead.