+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-33317 | |||||||||||||||||||||
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Title | human KCNQ1-CaM in complex with ML277 | |||||||||||||||||||||
Map data | ||||||||||||||||||||||
Sample |
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Keywords | potassium voltage-gated channel / ML277 / 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 / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / lumenal side of membrane / rhythmic behavior / negative regulation of voltage-gated potassium channel activity / 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 / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / lumenal side of membrane / rhythmic behavior / negative regulation of voltage-gated potassium channel activity / regulation of gastric acid secretion / stomach development / membrane repolarization during atrial cardiac muscle cell action potential / iodide transport / Phase 3 - rapid repolarisation / detection of mechanical stimulus involved in sensory perception of sound / membrane repolarization during action potential / regulation of atrial cardiac muscle cell membrane repolarization / Phase 2 - plateau phase / intracellular chloride ion homeostasis / membrane repolarization during ventricular cardiac muscle cell action potential / membrane repolarization during cardiac muscle cell action potential / negative regulation of delayed rectifier potassium channel activity / renal sodium ion absorption / potassium ion export across plasma membrane / 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 / positive regulation of potassium ion transmembrane transport / delayed rectifier potassium channel activity / Voltage gated Potassium channels / potassium ion homeostasis / outward rectifier potassium channel activity / ventricular cardiac muscle cell action potential / non-motile cilium assembly / 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 / monoatomic ion channel complex / ciliary base / positive regulation of cyclic-nucleotide phosphodiesterase activity / positive regulation of heart rate / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / regulation of heart contraction / adrenergic receptor signaling pathway / action potential / cochlea development / renal absorption / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-threonine phosphorylation / protein kinase A regulatory subunit binding / negative regulation of ryanodine-sensitive calcium-release channel activity / adenylate cyclase activator activity / protein phosphatase activator activity / potassium ion import across plasma membrane / regulation of heart rate by cardiac conduction / protein kinase A catalytic subunit binding / : / inner ear development / social behavior / adenylate cyclase binding / voltage-gated potassium channel activity / 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 / voltage-gated potassium channel complex / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction / : / phosphatidylinositol-4,5-bisphosphate binding / titin binding / positive regulation of protein autophosphorylation / regulation of calcium-mediated signaling / cellular response to cAMP / sperm midpiece / potassium ion transmembrane transport / transport vesicle / calcium channel complex / positive regulation of cardiac muscle contraction / cellular response to epinephrine stimulus / substantia nigra development / sarcomere / regulation of heart rate / protein serine/threonine kinase activator activity / erythrocyte differentiation / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / spindle microtubule / sensory perception of sound / response to insulin / cytoplasmic vesicle membrane / positive regulation of protein serine/threonine kinase activity / regulation of blood pressure / spindle pole / response to calcium ion Similarity search - Function | |||||||||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.6 Å | |||||||||||||||||||||
Authors | Ma D / Guo J | |||||||||||||||||||||
Funding support | China, 6 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_33317.map.gz | 45.5 MB | EMDB map data format | |
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Header (meta data) | emd-33317-v30.xml emd-33317.xml | 17 KB 17 KB | Display Display | EMDB header |
Images | emd_33317.png | 58.5 KB | ||
Filedesc metadata | emd-33317.cif.gz | 5.9 KB | ||
Others | emd_33317_half_map_1.map.gz emd_33317_half_map_2.map.gz | 37.1 MB 37.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-33317 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-33317 | HTTPS FTP |
-Validation report
Summary document | emd_33317_validation.pdf.gz | 813.2 KB | Display | EMDB validaton report |
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Full document | emd_33317_full_validation.pdf.gz | 812.8 KB | Display | |
Data in XML | emd_33317_validation.xml.gz | 11.6 KB | Display | |
Data in CIF | emd_33317_validation.cif.gz | 13.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-33317 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-33317 | HTTPS FTP |
-Related structure data
Related structure data | 7xnkMC 7xniC 7xnlC 7xnnC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_33317.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.014 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_33317_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_33317_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : KCNQ1-CaM in complex with ML277
Entire | Name: KCNQ1-CaM in complex with ML277 |
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Components |
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-Supramolecule #1: KCNQ1-CaM in complex with ML277
Supramolecule | Name: KCNQ1-CaM in complex with ML277 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Potassium voltage-gated channel subfamily KQT member 1
Macromolecule | Name: Potassium voltage-gated channel subfamily KQT member 1 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 76.487297 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: Calmodulin-3
Macromolecule | Name: Calmodulin-3 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 19.615445 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK LEGGSSGGLV P RGSGGSSG GHHHHHHHH UniProtKB: Calmodulin-3 |
-Macromolecule #3: POTASSIUM ION
Macromolecule | Name: POTASSIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: K |
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Molecular weight | Theoretical: 39.098 Da |
-Macromolecule #4: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-...
Macromolecule | Name: (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 |
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Molecular weight | Theoretical: 471.592 Da |
Chemical component information | ChemComp-I0S: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 200556 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |