8t50
Open human HCN1 F186C S264C bound to cAMP, reconstituted in LMNG + SPL
Structural highlights
DiseaseHCN1_HUMAN Early infantile epileptic encephalopathy. The disease is caused by mutations affecting the gene represented in this entry. FunctionHCN1_HUMAN Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). May mediate responses to sour stimuli.[1] Publication Abstract from PubMedHyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels. Structural basis for hyperpolarization-dependent opening of human HCN1 channel.,Burtscher V, Mount J, Huang J, Cowgill J, Chang Y, Bickel K, Chen J, Yuan P, Chanda B Nat Commun. 2024 Jun 18;15(1):5216. doi: 10.1038/s41467-024-49599-x. PMID:38890331[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
