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- EMDB-61642: Cryo-EM structure of human BKca channel-compound 10b complex -

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Basic information

Entry
Database: EMDB / ID: EMD-61642
TitleCryo-EM structure of human BKca channel-compound 10b complex
Map data
Sample
  • Complex: BKca channel-compound 10b complex
    • Protein or peptide: Calcium-activated potassium channel subunit alpha-1
  • Ligand: MAGNESIUM ION
  • Ligand: CALCIUM ION
  • Ligand: POTASSIUM ION
  • Ligand: 5-azanyl-2-[2,3,5,6-tetrakis(fluoranyl)-4-(trifluoromethyl)phenoxy]phenol
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsBKca channel / compound 10b / Cryo-EM / MEMBRANE PROTEIN
Function / homology
Function and homology information


Acetylcholine inhibits contraction of outer hair cells / micturition / Ca2+ activated K+ channels / large conductance calcium-activated potassium channel activity / response to carbon monoxide / 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 / micturition / Ca2+ activated K+ channels / large conductance calcium-activated potassium channel activity / response to carbon monoxide / 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 / positive regulation of apoptotic process / apical plasma membrane / identical protein binding / membrane / metal ion 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 / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsKim S / Park S / Lee NY / Lee EY / Lee N / Roh EC / Kim YG / Kim HJ / Jin MS / Park CS / Kim YC
Funding support Korea, Republic Of, 2 items
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, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61642.png

Downloads & links

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Map

FileDownload / File: emd_61642.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 250 pix.
= 270. Å		1.08 Å/pix.
x 250 pix.
= 270. Å		1.08 Å/pix.
x 250 pix.
= 270. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.172
Minimum - Maximum-0.20701848 - 0.6672611
Average (Standard dev.)0.013641136 (±0.0391915)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 270.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61642_half_map_1.map
Projections & Slices
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Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_61642_half_map_2.map
Projections & Slices
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Sample components

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Entire : BKca channel-compound 10b complex

EntireName: BKca channel-compound 10b complex
Components
  • Complex: BKca channel-compound 10b complex
    • Protein or peptide: Calcium-activated potassium channel subunit alpha-1
  • Ligand: MAGNESIUM ION
  • Ligand: CALCIUM ION
  • Ligand: POTASSIUM ION
  • Ligand: 5-azanyl-2-[2,3,5,6-tetrakis(fluoranyl)-4-(trifluoromethyl)phenoxy]phenol
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: BKca channel-compound 10b complex

SupramoleculeName: BKca channel-compound 10b complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Calcium-activated potassium channel subunit alpha-1

MacromoleculeName: Calcium-activated potassium channel subunit alpha-1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 126.049961 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDALIIPVTM EVPCDSRGQR MWWAFLASSM VTFFGGLFII LLWRTLKYLW TVCCHCGGKT KEAQKINNGS SQADGTLKPV DEKEEAVAA EVGWMTSVKD WAGVMISAQT LTGRVLVVLV FALSIGALVI YFIDSSNPIE SCQNFYKDFT LQIDMAFNVF F LLYFGLRF ...String:
MDALIIPVTM EVPCDSRGQR MWWAFLASSM VTFFGGLFII LLWRTLKYLW TVCCHCGGKT KEAQKINNGS SQADGTLKPV DEKEEAVAA EVGWMTSVKD WAGVMISAQT LTGRVLVVLV FALSIGALVI YFIDSSNPIE SCQNFYKDFT LQIDMAFNVF F LLYFGLRF IAANDKLWFW LEVNSVVDFF TVPPVFVSVY LNRSWLGLRF LRALRLIQFS EILQFLNILK TSNSIKLVNL LS IFISTWL TAAGFIHLVE NSGDPWENFQ NNQALTYWEC VYLLMVTMST VGYGDVYAKT TLGRLFMVFF ILGGLAMFAS YVP EIIELI GNRKKYGGSY SAVSGRKHIV VCGHITLESV SNFLKDFLHK DRDDVNVEIV FLHNISPNLE LEALFKRHFT QVEF YQGSV LNPHDLARVK IESADACLIL ANKYCADPDA EDASNIMRVI SIKNYHPKIR IITQMLQYHN KAHLLNIPSW NWKEG DDAI CLAELKLGFI AQSCLAQGLS TMLANLFSMR SFIKIEEDTW QKYYLEGVSN EMYTEYLSSA FVGLSFPTVC ELCFVK LKL LMIAIEYKSA NRESRILINP GNHLKIQEGT LGFFIASDAK EVKRAFFYCK ACHDDITDPK RIKKCGCKRP KMSIYKR MR RACCFDCGRS ERDCSCMSGR VRGNVDTLER AFPLSSVSVN DCSTSFRAFE DEQPSTLSPK KKQRNGGMRN SPNTSPKL M RHDPLLIPGN DQIDNMDSNV KKYDSTGMFH WCAPKEIEKV ILTRSEAAMT VLSGHVVVCI FGDVSSALIG LRNLVMPLR ASNFHYHELK HIVFVGSIEY LKREWETLHN FPKVSILPGT PLSRADLRAV NINLCDMCVI LSANQNNIDD TSLQDKECIL ASLNIKSMQ FDDSIGVLQA NSQGFTPPGM DRSSPDNSPV HGMLRQPSIT TGVNIPIITE LVNDTNVQFL DQDDDDDPDT E LYLTQPFA CGTAFAVSVL DSLMSATYFN DNILTLIRTL VTGGATPELE ALIAEENALR GGYSTPQTLA NRDRCRVAQL AL LDGPFAD LGDGGCYGDL FCKALKTYNM LCFGIYRLRD AHLSTPSQCT KRYVITNPPY EFELVPTDLI FCLMQFDHNA GQ

UniProtKB: Calcium-activated potassium channel subunit alpha-1

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Macromolecule #2: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #4: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: 5-azanyl-2-[2,3,5,6-tetrakis(fluoranyl)-4-(trifluoromethyl)phenox...

MacromoleculeName: 5-azanyl-2-[2,3,5,6-tetrakis(fluoranyl)-4-(trifluoromethyl)phenoxy]phenol
type: ligand / ID: 5 / Number of copies: 4 / Formula: A1L4E
Molecular weightTheoretical: 341.181 Da

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Macromolecule #6: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 6 / Number of copies: 16 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 59.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 414785
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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