Structural studies of ion channels: achievements, problems and perspectives

The superfamily of membrane proteins known as P-loop channels encompasses potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. An increasing number of crystal and cryo-EM structures are uncovering both general and specific features of these channels. Fundamental folding principles, the arrangement of structural segments, key residues that influence ionic selectivity, gating, and binding sites for toxins and medically relevant ligands have now been firmly established. The advent of AlphaFold2 (AF2) models represents another significant step in computationally predicting protein structures. Comparison of experimental P-loop channel structures with their corresponding AF2 models shows consistent folding patterns in experimentally resolved regions. Despite this remarkable progress, many crucial structural details, particularly important for predicting the outcomes of mutations and designing new medically relevant ligands, remain unresolved. Certain methodological challenges currently hinder the direct assessment of such details. Until the next methodological breakthrough occurs, a promising approach to analyzing ion channel structures in greater depth involves integrating various experimental and theoretical methods.