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- PDB-10ad: Cryo-EM structure of the human BK channel bound to the agonist NS1619 -

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Basic information

Entry
Database: PDB / ID: 10ad
TitleCryo-EM structure of the human BK channel bound to the agonist NS1619
ComponentsIsoform 5 of Calcium-activated potassium channel subunit alpha-1
KeywordsMEMBRANE PROTEIN / BK / Slo1
Function / homology
Function and homology information


micturition / Acetylcholine inhibits contraction of outer hair cells / large conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / calcium-activated potassium channel activity / negative regulation of cell volume / smooth muscle contraction involved in micturition / response to carbon monoxide / response to osmotic stress / Sensory processing of sound by inner hair cells of the cochlea ...micturition / Acetylcholine inhibits contraction of outer hair cells / large conductance calcium-activated potassium channel activity / Ca2+ activated K+ channels / calcium-activated potassium channel activity / negative regulation of cell volume / smooth muscle contraction involved in micturition / response to carbon monoxide / response to osmotic stress / Sensory processing of sound by inner hair cells of the cochlea / cGMP effects / intracellular potassium ion homeostasis / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / potassium ion transport / regulation of membrane potential / response to calcium ion / caveola / vasodilation / actin binding / postsynaptic membrane / response to hypoxia / apical plasma membrane / positive regulation of apoptotic process / membrane / metal ion binding / identical protein binding / plasma membrane
Similarity search - Function
: / Ca2+-activated K+ channel Slowpoke, TrkA_C like domain / Calcium-activated potassium channel BK, alpha subunit / : / Calcium-activated BK potassium channel alpha subunit / Calcium-activated potassium channel slowpoke-like RCK domain / Regulator of K+ conductance, N-terminal / RCK N-terminal domain profile. / Ion transport domain / Ion transport protein / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
: / Calcium-activated potassium channel subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsGonzalez-Sanabria, N. / Contreras, G.F. / Perozo, E. / Latorre, R.
Funding support United States, Chile, 4items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)1230265 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM150272 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM030376 United States
Agencia Nacional de Investigación y Desarrollo (ANID)21200592 Chile
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: The BK channel-NS1619 agonist complex reveals molecular insights into allosteric activation gating.
Authors: Naileth Gonzalez-Sanabria / Gustavo F Contreras / Maximiliano Rojas / Yorley Duarte / Fernando D Gonzalez-Nilo / Eduardo Perozo / Ramon Latorre /
Abstract: BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function ...BK channels play essential roles in a wealth of physiological functions, including regulating smooth muscle tone and neurotransmitter release. Its dysfunction, often caused by loss-of-function mutations, can lead to severe phenotypes, including ataxia and sensory impairment. Despite the therapeutic potential of BK channel agonists, the molecular mechanisms by which they stabilize the pore's open conformation remain unclear. Using cryoelectron microscopy and molecular dynamic simulations, we identified that NS1619, a synthetic benzimidazolone agonist, first described as a BK opener, binds within a pocket formed by the S6/RCK1 linker and the S4 transmembrane segment. Our simulations suggest that agonist binding promotes a twisting motion in the S6 segment, enabling critical interactions with residues K330, K331, and F223. These findings provide a molecular model for the mechanism of NS1619 and suggest that its binding site can accommodate other agonists, highlighting a promising target for therapeutic development.
History
DepositionJan 8, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 4, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 11, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Feb 11, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Isoform 5 of Calcium-activated potassium channel subunit alpha-1
C: Isoform 5 of Calcium-activated potassium channel subunit alpha-1
D: Isoform 5 of Calcium-activated potassium channel subunit alpha-1
A: Isoform 5 of Calcium-activated potassium channel subunit alpha-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)503,24220
Polymers501,3754
Non-polymers1,86716
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Isoform 5 of Calcium-activated potassium channel subunit alpha-1 / BK channel / BKCA alpha / Calcium-activated potassium channel / subfamily M subunit alpha-1 / K(VCA) ...BK channel / BKCA alpha / Calcium-activated potassium channel / subfamily M subunit alpha-1 / K(VCA)alpha / KCa1.1 / Maxi K channel / MaxiK / Slo-alpha / Slo1 / Slowpoke homolog / Slo homolog / hSlo


Mass: 125343.727 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNMA1, KCNMA, SLO / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q12791
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-A1E02 / 3-[2-oxidanyl-5-(trifluoromethyl)phenyl]-6-(trifluoromethyl)-1~{H}-benzimidazol-2-one


Mass: 362.227 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H8F6N2O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: hBK NS1619 complex / Type: COMPLEX
Details: Cryo-EM sample of the human BK (KCNMA1) channel in complex with the synthetic agonist NS1619
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GnTI-
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris-HClTris-HCl1
2320 mMPotassium chlorideKCl1
310 mMMagnesium chlorideMgCl21
410 mMCalcium chlorideCaCl21
52 mMTris(2-carboxyethyl)phosphineTCEP1
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
9cryoSPARCinitial Euler assignment
11cryoSPARCclassification
12Coot3D reconstruction
13PHENIX1.21.2_5419model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90000 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6V22

6v22


Accession code: 6V22 / Source name: PDB / Type: experimental model

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