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- EMDB-75629: Human Slo1-Paxilline complex under divalent chelated condition - ... -

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Basic information

Entry
Database: EMDB / ID: EMD-75629
TitleHuman Slo1-Paxilline complex under divalent chelated condition - gating-ring masked
Map dataUnharpened gating-ring masked map of hSlo1-paxilline complex
Sample
  • Complex: human Slo1 in complex with an indole diterpene alkaloid, paxilline
    • Protein or peptide: Calcium-activated potassium channel subunit alpha-1
  • Ligand: POTASSIUM ION
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: Digitonin
  • Ligand: CHOLESTEROL
  • Ligand: Paxilline
  • Ligand: water
KeywordsBK / human BK / hSlo1 / penitrem A / ion channel / MEMBRANE PROTEIN / MEMBRANE PROTEIN-TOXIN complex
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 / potassium ion transport / voltage-gated potassium channel activity / voltage-gated potassium channel complex / potassium ion transmembrane transport / regulation of membrane potential / response to calcium ion / vasodilation / caveola / actin binding / response to hypoxia / postsynaptic membrane / apical plasma membrane / positive regulation of apoptotic process / membrane / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.71 Å
AuthorsChowdhury S / Pal K / Kallure GS
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM145719 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Structural underpinnings of human Slo1 inhibition by scorpion and fungal toxins.
Authors: Gopal S Kallure / Kamalendu Pal / Gabriel W Prather / Sandipan Chowdhury /
Abstract: Slo1 channels regulate key electrochemical signaling events in a variety of excitable and nonexcitable cells. Here, we have investigated the mechanisms by which distinct small molecules inhibit human ...Slo1 channels regulate key electrochemical signaling events in a variety of excitable and nonexcitable cells. Here, we have investigated the mechanisms by which distinct small molecules inhibit human Slo1 (hSlo1) channel activity using single-particle cryo-EM, liposome flux, and toxin-binding assays. We find that unlike classical permeation blockers like scorpion toxins, indole diterpene (ID) class of fungal mycotoxins, paxilline and penitrem A, are ensconced in a binding pocket, deep within the putatively closed hSlo1 pore and sterically restrict its opening. Binding of paxilline to its gating inhibition site dramatically slows dissociation of a fluorescent charybdotoxin derivative, via an allosteric mechanism that likely involves a key residue on the S5 helix (W246). Although four paxilline molecules may concurrently engage the hSlo1 pore, binding of <4 molecules is sufficient for efficacious inhibition of channel opening but inefficient at arresting toxin dissociation. We also find evidence that under divalent and ID free conditions, the ID binding pocket of hSlo1 is occluded by lipids that extend into the hSlo1 pore lumen through interhelical crevices that become constricted in the divalent bound open state. These lipids may not only competitively regulate ID binding but also tune the energetics of channel gating, sterically or by altering the hydration state of the pore vestibule. Our study provides a framework to understand fundamental Slo1 gating mechanisms and aid future developments of therapeutically beneficial small molecule Slo1 inhibitors.
History
DepositionFeb 18, 2026-
Header (metadata) releaseSep 23, 2026-
Map releaseSep 23, 2026-
UpdateSep 23, 2026-
Current statusSep 23, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75629.png

Downloads & links

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Map

FileDownload / File: emd_75629.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationUnharpened gating-ring masked map of hSlo1-paxilline complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 280 pix.
= 291.2 Å		1.04 Å/pix.
x 280 pix.
= 291.2 Å		1.04 Å/pix.
x 280 pix.
= 291.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.19871755 - 0.43792117
Average (Standard dev.)0.0014690227 (±0.012667761)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 291.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_75629_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened gating-ring masked map of hSlo1-paxilline complex

Fileemd_75629_additional_1.map
AnnotationSharpened gating-ring masked map of hSlo1-paxilline complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map A

Fileemd_75629_half_map_1.map
AnnotationHalf-map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map B

Fileemd_75629_half_map_2.map
AnnotationHalf-map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human Slo1 in complex with an indole diterpene alkaloid, paxilline

EntireName: human Slo1 in complex with an indole diterpene alkaloid, paxilline
Components
  • Complex: human Slo1 in complex with an indole diterpene alkaloid, paxilline
    • Protein or peptide: Calcium-activated potassium channel subunit alpha-1
  • Ligand: POTASSIUM ION
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • Ligand: Digitonin
  • Ligand: CHOLESTEROL
  • Ligand: Paxilline
  • Ligand: water

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Supramolecule #1: human Slo1 in complex with an indole diterpene alkaloid, paxilline

SupramoleculeName: human Slo1 in complex with an indole diterpene alkaloid, paxilline
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: 119.988062 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 RIKKCGCKRL EDEQPST LS PKKKQRNGGM RNSPNTSPKL MRHDPLLIPG NDQIDNMDSN VKKYDSTGMF HWCAPKEIEK VILTRSEAAM TVLSGHVV V CIFGDVSSAL IGLRNLVMPL RASNFHYHEL KHIVFVGSIE YLKREWETLH NFPKVSILPG TPLSRADLRA VNINLCDMC VILSANQNNI DDTSLQDKEC ILASLNIKSM QFDDSIGVLQ ANSQGFTPPG MDRSSPDNSP VHGMLRQPSI TTGVNIPIIT ELVNDTNVQ FLDQDDDDDP DTELYLTQPF ACGTAFAVSV LDSLMSATYF NDNILTLIRT LVTGGATPEL EALIAEENAL R GGYSTPQT LANRDRCRVA QLALLDGPFA DLGDGGCYGD LFCKALKTYN MLCFGIYRLR DAHLSTPSQC TKRYVITNPP YE FELVPTD LIFCLMQFDS NSLEVLFQ

UniProtKB: Calcium-activated potassium channel subunit alpha-1

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Macromolecule #2: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 2 / Number of copies: 5 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #3: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 3 / Number of copies: 28 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

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Macromolecule #4: Digitonin

MacromoleculeName: Digitonin / type: ligand / ID: 4 / Number of copies: 36 / Formula: AJP
Molecular weightTheoretical: 1.229312 KDa
Chemical component information

ChemComp-AJP:
Digitonin / detergent*YM

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: Paxilline

MacromoleculeName: Paxilline / type: ligand / ID: 6 / Number of copies: 4 / Formula: A1C9G
Molecular weightTheoretical: 435.555 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 72.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.71 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 359852
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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