8T4Y

Human HCN1 F186C S264C C309A bound to cAMP, reconstituted in LMNG + SPL

Summary for 8T4Y

• Entry DOI: 10.2210/pdb8t4y/pdb
• Related: 8T4M
• EMDB information: 41036 41040 41041
• Descriptor: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE (2 entities in total)
• Functional Keywords: membrane protein, ion channel, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 396675.86

Authors

Burtscher, V.,Mount, J.,Cowgill, J.,Chang, Y.,Bickel, K.,Yuan, P.,Chanda, B. (deposition date: 2023-06-12, release date: 2024-06-19, Last modification date: 2024-07-03)

Primary citation

Burtscher, V.,Mount, J.,Huang, J.,Cowgill, J.,Chang, Y.,Bickel, K.,Chen, J.,Yuan, P.,Chanda, B.
Structural basis for hyperpolarization-dependent opening of human HCN1 channel.
Nat Commun, 15:5216-5216, 2024

PubMed Abstract: Hyperpolarization 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.

PubMed: 38890331
DOI: 10.1038/s41467-024-49599-x

Experimental method

ELECTRON MICROSCOPY (3.58 Å)