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- EMDB-33319: human KCNQ1-CaM-ML277-PIP2 complex in state B -

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Basic information

Entry
Database: EMDB / ID: EMD-33319
Titlehuman KCNQ1-CaM-ML277-PIP2 complex in state B
Map data
Sample
  • Organelle or cellular component: human KCNQ1-CaM-ML277-PIP2 complex in state B
    • Protein or peptide: Calmodulin-3
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
  • Ligand: POTASSIUM ION
  • Ligand: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
Keywordspotassium voltage-gated channel / ML277 / PIP2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / basolateral part of cell / lumenal side of membrane / negative regulation of voltage-gated potassium channel activity / rhythmic behavior / iodide transport / regulation of gastric acid secretion / stomach development ...gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / basolateral part of cell / lumenal side of membrane / negative regulation of voltage-gated potassium channel activity / rhythmic behavior / iodide transport / regulation of gastric acid secretion / stomach development / membrane repolarization during atrial cardiac muscle cell action potential / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / Phase 3 - rapid repolarisation / membrane repolarization during action potential / regulation of atrial cardiac muscle cell membrane repolarization / Phase 2 - plateau phase / membrane repolarization during ventricular cardiac muscle cell action potential / intracellular chloride ion homeostasis / negative regulation of delayed rectifier potassium channel activity / membrane repolarization during cardiac muscle cell action potential / renal sodium ion absorption / potassium ion export across plasma membrane / detection of mechanical stimulus involved in sensory perception of sound / atrial cardiac muscle cell action potential / auditory receptor cell development / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of membrane repolarization / protein phosphatase 1 binding / delayed rectifier potassium channel activity / positive regulation of potassium ion transmembrane transport / Voltage gated Potassium channels / ventricular cardiac muscle cell action potential / potassium ion homeostasis / non-motile cilium assembly / outward rectifier potassium channel activity / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell contraction / intestinal absorption / inner ear morphogenesis / negative regulation of high voltage-gated calcium channel activity / negative regulation of calcium ion export across plasma membrane / adrenergic receptor signaling pathway / presynaptic endocytosis / regulation of heart contraction / renal absorption / regulation of cardiac muscle cell action potential / negative regulation of peptidyl-threonine phosphorylation / cochlea development / calcineurin-mediated signaling / positive regulation of ryanodine-sensitive calcium-release channel activity / ciliary base / regulation of cell communication by electrical coupling involved in cardiac conduction / protein kinase A regulatory subunit binding / negative regulation of ryanodine-sensitive calcium-release channel activity / potassium ion import across plasma membrane / protein kinase A catalytic subunit binding / social behavior / monoatomic ion channel complex / regulation of heart rate by cardiac conduction / inner ear development / protein phosphatase activator activity / adenylate cyclase binding / voltage-gated potassium channel activity / action potential / catalytic complex / regulation of cardiac muscle contraction / detection of calcium ion / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / positive regulation of heart rate / positive regulation of protein autophosphorylation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction / transport vesicle / regulation of calcium-mediated signaling / titin binding / cellular response to cAMP / voltage-gated potassium channel complex / sperm midpiece / cellular response to epinephrine stimulus / calcium channel complex / phosphatidylinositol-4,5-bisphosphate binding / potassium ion transmembrane transport / substantia nigra development / positive regulation of peptidyl-threonine phosphorylation / calyx of Held / cytoplasmic vesicle membrane / positive regulation of cardiac muscle contraction / adenylate cyclase activator activity / regulation of heart rate / sarcomere / protein serine/threonine kinase activator activity / erythrocyte differentiation / regulation of cytokinesis / positive regulation of protein serine/threonine kinase activity / spindle microtubule / response to insulin / sensory perception of sound / regulation of blood pressure / spindle pole
Similarity search - Function
Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. ...Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair
Similarity search - Domain/homology
Calmodulin-3 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsMa D / Guo J
Funding support China, 6 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2020YFA0908501 China
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
National Natural Science Foundation of China (NSFC)31870724 China
National Natural Science Foundation of China (NSFC)81800231 China
Other governmentLR19C050002
Other government2021FZZX001-28
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.
Authors: Demin Ma / Ling Zhong / Zhenzhen Yan / Jing Yao / Yan Zhang / Fan Ye / Yuan Huang / Dongwu Lai / Wei Yang / Panpan Hou / Jiangtao Guo /
Abstract: The cardiac KCNQ1 potassium channel carries the important current and controls the heart rhythm. Hundreds of mutations in KCNQ1 can cause life-threatening cardiac arrhythmia. Although KCNQ1 ...The cardiac KCNQ1 potassium channel carries the important current and controls the heart rhythm. Hundreds of mutations in KCNQ1 can cause life-threatening cardiac arrhythmia. Although KCNQ1 structures have been recently resolved, the structural basis for the dynamic electro-mechanical coupling, also known as the voltage sensor domain-pore domain (VSD-PD) coupling, remains largely unknown. In this study, utilizing two VSD-PD coupling enhancers, namely, the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP) and a small-molecule ML277, we determined 2.5-3.5 Å resolution cryo-electron microscopy structures of full-length human KCNQ1-calmodulin (CaM) complex in the apo closed, ML277-bound open, and ML277-PIP-bound open states. ML277 binds at the "elbow" pocket above the S4-S5 linker and directly induces an upward movement of the S4-S5 linker and the opening of the activation gate without affecting the C-terminal domain (CTD) of KCNQ1. PIP binds at the cleft between the VSD and the PD and brings a large structural rearrangement of the CTD together with the CaM to activate the PD. These findings not only elucidate the structural basis for the dynamic VSD-PD coupling process during KCNQ1 gating but also pave the way to develop new therapeutics for anti-arrhythmia.
History
DepositionApr 29, 2022-
Header (metadata) releaseDec 14, 2022-
Map releaseDec 14, 2022-
UpdateJul 3, 2024-
Current statusJul 3, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33319.png

Downloads & links

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Map

FileDownload / File: emd_33319.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 240 pix.
= 243.36 Å		1.01 Å/pix.
x 240 pix.
= 243.36 Å		1.01 Å/pix.
x 240 pix.
= 243.36 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0081
Minimum - Maximum-0.046429902 - 0.09565838
Average (Standard dev.)-0.00004467735 (±0.0023062774)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 243.36002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33319_half_map_1.map
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Half map: #2

Fileemd_33319_half_map_2.map
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Sample components

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Entire : human KCNQ1-CaM-ML277-PIP2 complex in state B

EntireName: human KCNQ1-CaM-ML277-PIP2 complex in state B
Components
  • Organelle or cellular component: human KCNQ1-CaM-ML277-PIP2 complex in state B
    • Protein or peptide: Calmodulin-3
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
  • Ligand: POTASSIUM ION
  • Ligand: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Supramolecule #1: human KCNQ1-CaM-ML277-PIP2 complex in state B

SupramoleculeName: human KCNQ1-CaM-ML277-PIP2 complex in state B / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Calmodulin-3

MacromoleculeName: Calmodulin-3 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 19.615445 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK LEGGSSGGLV P RGSGGSSG GHHHHHHHH

UniProtKB: Calmodulin-3

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Macromolecule #2: Potassium voltage-gated channel subfamily KQT member 1

MacromoleculeName: Potassium voltage-gated channel subfamily KQT member 1
type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.487297 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAASSPPRA ERKRWGWGRL PGARRGSAGL AKKCPFSLEL AEGGPAGGAL YAPIAPGAPG PAPPASPAAP AAPPVASDLG PRPPVSLDP RVSIYSTRRP VLARTHVQGR VYNFLERPTG WKCFVYHFAV FLIVLVCLIF SVLSTIEQYA ALATGTLFWM E IVLVVFFG ...String:
MAAASSPPRA ERKRWGWGRL PGARRGSAGL AKKCPFSLEL AEGGPAGGAL YAPIAPGAPG PAPPASPAAP AAPPVASDLG PRPPVSLDP RVSIYSTRRP VLARTHVQGR VYNFLERPTG WKCFVYHFAV FLIVLVCLIF SVLSTIEQYA ALATGTLFWM E IVLVVFFG TEYVVRLWSA GCRSKYVGLW GRLRFARKPI SIIDLIVVVA SMVVLCVGSK GQVFATSAIR GIRFLQILRM LH VDRQGGT WRLLGSVVFI HRQELITTLY IGFLGLIFSS YFVYLAEKDA VNESGRVEFG SYADALWWGV VTVTTIGYGD KVP QTWVGK TIASCFSVFA ISFFALPAGI LGSGFALKVQ QKQRQKHFNR QIPAAASLIQ TAWRCYAAEN PDSSTWKIYI RKAP RSHTL LSPSPKPKKS VVVKKKKFKL DKDNGVTPGE KMLTVPHITC DPPEERRLDH FSVDGYDSSV RKSPTLLEVS MPHFM RTNS FAEDLDLEGE TLLTPITHIS QLREHHRATI KVIRRMQYFV AKKKFQQARK PYDVRDVIEQ YSQGHLNLMV RIKELQ RRL DQSIGKPSLF ISVSEKSKDR GSNTIGARLN RVEDKVTQLD QRLALITDML HQLLSLHGGS TPGSGGPPRE GGAHITQ PC GSGGSVDPEL FLPSNTLPTY EQLTVPRRGP DEGSLEGGSS GGWSHPQFEK

UniProtKB: Potassium voltage-gated channel subfamily KQT member 1

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Macromolecule #3: POTASSIUM ION

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

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Macromolecule #4: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-...

MacromoleculeName: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide
type: ligand / ID: 4 / Number of copies: 4 / Formula: I0S
Molecular weightTheoretical: 471.592 Da
Chemical component information

ChemComp-I0S:
(2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide

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Macromolecule #5: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
type: ligand / ID: 5 / Number of copies: 4 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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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 K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: -1.3 µm / Nominal defocus min: -1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6uzz

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 257550
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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