6uqf | pdb_00006uqf
Human HCN1 channel in a hyperpolarized conformation
Structural highlights
Disease[HCN1_HUMAN] Early infantile epileptic encephalopathy. The disease is caused by mutations affecting the gene represented in this entry. Function[HCN1_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 PubMedThe hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a voltage-gated cation channel that mediates neuronal and cardiac pacemaker activity. The HCN channel exhibits reversed voltage dependence, meaning it closes with depolarization and opens with hyperpolarization. Different from Na(+), Ca(2+), and Kv1-Kv7 channels, the HCN channel does not have domain-swapped voltage sensors. We introduced a reversible, metal-mediated cross bridge into the voltage sensors to create the chemical equivalent of a hyperpolarized conformation and determined the structure using cryoelectron microscopy (cryo-EM). Unlike the depolarized HCN channel, the S4 helix is displaced toward the cytoplasm by two helical turns. Near the cytoplasm, the S4 helix breaks into two helices, one running parallel to the membrane surface, analogous to the S4-S5 linker of domain-swapped voltage-gated channels. These findings suggest a basis for allosteric communication between voltage sensors and the gate in this kind of channel. They also imply that voltage sensor movements are not the same in all voltage-gated channels. Voltage Sensor Movements during Hyperpolarization in the HCN Channel.,Lee CH, MacKinnon R Cell. 2019 Dec 12;179(7):1582-1589.e7. doi: 10.1016/j.cell.2019.11.006. Epub 2019, Nov 28. PMID:31787376[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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