5u6p | pdb_00005u6p
Structure of the human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
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 PubMedHyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the control of rhythmic activity in cardiac and neuronal pacemaker cells. In HCN, the polarity of voltage dependence is uniquely reversed. Intracellular cyclic adenosine monophosphate (cAMP) levels tune the voltage response, enabling sympathetic nerve stimulation to increase the heart rate. We present cryo-electron microscopy structures of the human HCN channel in the absence and presence of cAMP at 3.5 A resolution. HCN channels contain a K+ channel selectivity filter-forming sequence from which the amino acids create a unique structure that explains Na+ and K+ permeability. The voltage sensor adopts a depolarized conformation, and the pore is closed. An S4 helix of unprecedented length extends into the cytoplasm, contacts the C-linker, and twists the inner helical gate shut. cAMP binding rotates cytoplasmic domains to favor opening of the inner helical gate. These structures advance understanding of ion selectivity, reversed polarity gating, and cAMP regulation in HCN channels. Structures of the Human HCN1 Hyperpolarization-Activated Channel.,Lee CH, MacKinnon R Cell. 2017 Jan 12;168(1-2):111-120.e11. doi: 10.1016/j.cell.2016.12.023. Epub, 2017 Jan 12. PMID:28086084[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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