Abstract
HCN channels (HCN1-4) generate the If current that controls automaticity and rhythm of the heartbeat. Using single-particle electron cryo-microscopy (cryo-EM), we obtained the structure of HCN4, bound and unbound to the cAMP ligand and with the pore in open and closed configuration. Analysis of the structures reveals a coordination site for the Mg2+ ion which, by linking two domains of the protein, facilitates channel gating by cyclic nucleotides. The open pore configuration used in molecular dynamics simulations provided information on the mechanisms of permeation of K+/Na+ ions and on the mechanism of action of ivabradine, a drug used in the treatment of angina.
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