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- PDB-9jo4: Cryo-EM structure of human BKca channel-compound 51b complex -

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Basic information

Entry
Database: PDB / ID: 9jo4
TitleCryo-EM structure of human BKca channel-compound 51b complex
ComponentsCalcium-activated potassium channel subunit alpha-1
KeywordsMEMBRANE PROTEIN / BKca channel / compound 51b / Cryo-EM
Function / homology
Function and homology information


Acetylcholine inhibits contraction of outer hair cells / Ca2+ activated K+ channels / micturition / response to carbon monoxide / large conductance calcium-activated potassium channel activity / calcium-activated potassium channel activity / negative regulation of cell volume / smooth muscle contraction involved in micturition / intracellular potassium ion homeostasis / Sensory processing of sound by inner hair cells of the cochlea ...Acetylcholine inhibits contraction of outer hair cells / Ca2+ activated K+ channels / micturition / response to carbon monoxide / large conductance calcium-activated potassium channel activity / calcium-activated potassium channel activity / negative regulation of cell volume / smooth muscle contraction involved in micturition / intracellular potassium ion homeostasis / Sensory processing of sound by inner hair cells of the cochlea / response to osmotic stress / cGMP effects / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / regulation of membrane potential / potassium ion transport / caveola / response to calcium ion / vasodilation / actin binding / postsynaptic membrane / response to hypoxia / apical plasma membrane / positive regulation of apoptotic process / metal ion binding / identical protein binding / membrane / 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 / RCK N-terminal domain profile. / Ion transport domain / Ion transport protein / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
: / : / CHOLESTEROL HEMISUCCINATE / Calcium-activated potassium channel subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKim, S. / Park, S. / Lee, N.Y. / Lee, E.Y. / Lee, N. / Roh, E.C. / Kim, Y.G. / Kim, H.J. / Jin, M.S. / Park, C.S. / Kim, Y.C.
Funding support Korea, Republic Of, 2items
OrganizationGrant numberCountry
Other governmentRS-2023-00258812 Korea, Republic Of
National Research Foundation (NRF, Korea)RS-2024-00411137 Korea, Republic Of
CitationJournal: J Med Chem / Year: 2025
Title: Discovery of Diphenyl Ether Derivatives as Novel BK Channel Activators: Structure-Activity Relationship, Cryo-EM Complex Structures, and Animal Studies.
Authors: Soo Bin Park / Na Young Lee / Eun-Young Lee / Subin Kim / Narasaem Lee / Eun Chae Roh / Yoon Gyoon Kim / Hee Jin Kim / Mi Sun Jin / Chul-Seung Park / Yong-Chul Kim /
Abstract: The BK channel, a large-conductance calcium-activated potassium channel, plays a crucial role in maintaining the homeostasis of the micturition cycle and airway-related functions. In this study, we ...The BK channel, a large-conductance calcium-activated potassium channel, plays a crucial role in maintaining the homeostasis of the micturition cycle and airway-related functions. In this study, we optimized a novel BK channel activator, , with a diphenyl ether structure identified from library screening. This led to the discovery of potent activators, (EC = 0.12 μM, cell-based assay) and , an orally bioavailable derivative. Compound demonstrated potent efficacy in a spontaneous hypertensive rat (SHR) of urinary incontinence model, while compound showed dose-dependent cough suppression efficacy with an ED of 11.8 mg/kg in a citric acid-induced cough model. Furthermore, we reported the cryo-electron microscopy (cryo-EM) structures of the BK channel in complex with and at resolutions of 2.8 and 3.4 Å. Based on structural analyses, we determined the binding sites and key interaction residues of , which were validated via mutation studies.
History
DepositionSep 24, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 26, 2025Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 26, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.1Mar 12, 2025Data 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Calcium-activated potassium channel subunit alpha-1
B: Calcium-activated potassium channel subunit alpha-1
C: Calcium-activated potassium channel subunit alpha-1
D: Calcium-activated potassium channel subunit alpha-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)512,47439
Polymers502,1664
Non-polymers10,30835
Water00
1


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

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
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: 125541.461 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): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q12791

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Non-polymers , 5 types, 35 molecules

#2: Chemical
ChemComp-A1L4F / 5-(5-morpholin-4-ylpentylamino)-2-[2,3,5,6-tetrakis(fluoranyl)-4-(trifluoromethyl)phenoxy]phenol


Mass: 496.418 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H23F7N2O3
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C31H50O4

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Details

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: BKca channel-compound 51b complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107778 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00729988
ELECTRON MICROSCOPYf_angle_d0.64340796
ELECTRON MICROSCOPYf_dihedral_angle_d15.4254424
ELECTRON MICROSCOPYf_chiral_restr0.0444685
ELECTRON MICROSCOPYf_plane_restr0.0035030

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