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- EMDB-73857: Human HCN1 in complex with cAMP in nanodisc -

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Basic information

Entry
Database: EMDB / ID: EMD-73857
TitleHuman HCN1 in complex with cAMP in nanodisc
Map data
Sample
  • Complex: Homotetrameric HCN1 complex (fusion with Thermostable Green Protein)
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1,Thermostable Green Protein
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE
Keywordsion channel / pacemaker channel / hyperpolarization-activated / MEMBRANE PROTEIN
Function / homology
Function and homology information


: / positive regulation of membrane hyperpolarization / HCN channels / general adaptation syndrome, behavioral process / HCN channel complex / retinal cone cell development / intracellularly cAMP-activated cation channel activity / negative regulation of action potential / regulation of SA node cell action potential / maternal behavior ...: / positive regulation of membrane hyperpolarization / HCN channels / general adaptation syndrome, behavioral process / HCN channel complex / retinal cone cell development / intracellularly cAMP-activated cation channel activity / negative regulation of action potential / regulation of SA node cell action potential / maternal behavior / apical dendrite / sodium ion import across plasma membrane / apical protein localization / response to L-glutamate / negative regulation of synaptic transmission, glutamatergic / voltage-gated sodium channel activity / voltage-gated monoatomic cation channel activity / regulation of membrane depolarization / potassium ion import across plasma membrane / phosphatidylinositol-3,4,5-trisphosphate binding / regulation of heart rate by cardiac conduction / voltage-gated potassium channel activity / potassium channel activity / cAMP binding / neuronal action potential / cellular response to interferon-beta / phosphatidylinositol-4,5-bisphosphate binding / presynaptic active zone membrane / potassium ion transmembrane transport / dendrite membrane / axon terminus / cellular response to cAMP / dendritic shaft / sodium ion transmembrane transport / regulation of membrane potential / response to calcium ion / protein homotetramerization / basolateral plasma membrane / postsynaptic membrane / axon / neuronal cell body / dendrite / glutamatergic synapse / cell surface / identical protein binding / plasma membrane
Similarity search - Function
Ion transport N-terminal / Ion transport protein N-terminal / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain ...Ion transport N-terminal / Ion transport protein N-terminal / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / RmlC-like jelly roll fold / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsChinn A / Chanda B
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS116850 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)DP2GM140920 United States
National Science Foundation (NSF, United States)CHE-1856518 United States
CitationJournal: Nat Commun / Year: 2026
Title: Lipid bilayers determine allostery but not intrinsic affinity of cAMP to pacemaker channels.
Authors: Vinay Idikuda / Susovan Roy Chowdhury / Audrey Chinn / Yongchang Chang / Suhaila Rahman / Qian Ren / Huan Bao / Ziao Fu / Randall H Goldsmith / Baron Chanda /
Abstract: The binding of cyclic adenosine monophosphate (cAMP) to hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels regulates cardiac pacemaking but key aspects of the mechanism of ligand- ...The binding of cyclic adenosine monophosphate (cAMP) to hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels regulates cardiac pacemaking but key aspects of the mechanism of ligand-dependent regulation remain unresolved. Here, we examine the role of the lipid environment by reconstituting purified human HCN channels into lipid nanodiscs and measuring successive cAMP binding to single HCN channels using nanophotonic waveguides. Regardless of nanodisc size or lipid composition, cAMP molecules bind cooperatively to HCN channels in lipid bilayers, unlike channels solubilized in detergents. The affinity of the first ligand remains unchanged across conditions, indicating that the bilayer selectively alters higher-order ligation states. Cryo-EM structures of apo- and holo-HCN channels reveal additional lipid densities that are weak or absent in detergent-solubilized preparations. Together, these findings show that the lipid bilayer is both necessary and sufficient to induce cooperative ligand binding in HCN channels, thereby enhancing their sensitivity to gating stimuli.
History
DepositionNov 14, 2025-
Header (metadata) releaseMay 20, 2026-
Map releaseMay 20, 2026-
UpdateMay 20, 2026-
Current statusMay 20, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73857.png

Downloads & links

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Map

FileDownload / File: emd_73857.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 320 pix.
= 303.2 Å		0.95 Å/pix.
x 320 pix.
= 303.2 Å		0.95 Å/pix.
x 320 pix.
= 303.2 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9475 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.21
Minimum - Maximum-1.1148158 - 2.0645
Average (Standard dev.)0.0016402022 (±0.048653662)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 303.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_73857_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_73857_half_map_2.map
Projections & Slices
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Sample components

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Entire : Homotetrameric HCN1 complex (fusion with Thermostable Green Protein)

EntireName: Homotetrameric HCN1 complex (fusion with Thermostable Green Protein)
Components
  • Complex: Homotetrameric HCN1 complex (fusion with Thermostable Green Protein)
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1,Thermostable Green Protein
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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Supramolecule #1: Homotetrameric HCN1 complex (fusion with Thermostable Green Protein)

SupramoleculeName: Homotetrameric HCN1 complex (fusion with Thermostable Green Protein)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...

MacromoleculeName: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1,Thermostable Green Protein
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 103.035594 KDa
Recombinant expressionOrganism: Komagataella pastoris (fungus)
SequenceString: MDYKDDDDKG SEGGGKPNSS SNSRDDGNSV FPAKASATGA GPAAAEKRLG TPPGGGGAGA KEHGNSVCFK VDGGGGGGGG GGGGEEPAG GFEDAEGPRR QYGFMQRQFT SMLQPGVNKF SLRMFGSQKA VEKEQERVKT AGFWIIHPYS DFRFYWDLIM L IMMVGNLV ...String:
MDYKDDDDKG SEGGGKPNSS SNSRDDGNSV FPAKASATGA GPAAAEKRLG TPPGGGGAGA KEHGNSVCFK VDGGGGGGGG GGGGEEPAG GFEDAEGPRR QYGFMQRQFT SMLQPGVNKF SLRMFGSQKA VEKEQERVKT AGFWIIHPYS DFRFYWDLIM L IMMVGNLV IIPVGITFFT EQTTTPWIIF NVASDTVFLL DLIMNFRTGT VNEDSSEIIL DPKVIKMNYL KSWFVVDFIS SI PVDYIFL IVEKGMDSEV YKTARALRIV RFTKILSLLR LLRLSRLIRY IHQWEEIFHM TYDLASAVVR IFNLIGMMLL LCH WDGCLQ FLVPLLQDFP PDCWVSLNEM VNDSWGKQYS YALFKAMSHM LCIGYGAQAP VSMSDLWITM LSMIVGATCY AMFV GHATA LIQSLDSSRR QYQEKYKQVE QYMSFHKLPA DMRQKIHDYY EHRYQGKIFD EENILNELND PLREEIVNFN CRKLV ATMP LFANADPNFV TAMLSKLRFE VFQPGDYIIR EGAVGKKMYF IQHGVAGVIT KSSKEMKLTD GSYFGEICLL TKGRRT ASV RADTYCRLYS LSVDNFNEVL EEYPMMRRAF ETVAIDRLDR IGKKNSILLQ KFQKDLNTGV FNNQENEILK QIVKHDR EM VQAASNSGLN DIFEAQKIEW HELEVLFQGP TAAMSVIKPE MKIKLRMEGA VNGHKFVIEG EGIGKPYEGT QTLDLTVE E GAPLPFSYDI LTPAFQYGNR AFTKYPEDIP DYFKQAFPEG YSWERSMTYE DQGICIATSD ITMEGDCFFY EIRFDGTNF PPNGPVMQKK TLKWEPSTEK MYVEDGVLKG DVEMALLLEG GGHYRCDFKT TYKAKKDVRL PDAHEVDHRI EILSHDKDYN KVRLYEHAE ARYSGGGHHH HHHHHHH

UniProtKB: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1

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Macromolecule #2: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

MacromoleculeName: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: CMP
Molecular weightTheoretical: 329.206 Da
Chemical component information

ChemComp-CMP:
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 113803
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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