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- PDB-7xnl: human KCNQ1-CaM-ML277-PIP2 complex in state A -

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Basic information

Entry
Database: PDB / ID: 7xnl
Titlehuman KCNQ1-CaM-ML277-PIP2 complex in state A
Components
  • Calmodulin-3
  • Potassium voltage-gated channel subfamily KQT member 1
KeywordsMEMBRANE PROTEIN / potassium voltage-gated channel / ML277 / PIP2
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 / negative regulation of voltage-gated potassium channel activity / basolateral part of cell / lumenal side of membrane / negative regulation of delayed rectifier potassium channel activity / rhythmic behavior / stomach development / regulation of gastric acid secretion ...gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / negative regulation of voltage-gated potassium channel activity / basolateral part of cell / lumenal side of membrane / negative regulation of delayed rectifier potassium channel activity / rhythmic behavior / stomach development / regulation of gastric acid secretion / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / Phase 3 - rapid repolarisation / membrane repolarization during action potential / membrane repolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / iodide transport / regulation of atrial cardiac muscle cell membrane repolarization / membrane repolarization during ventricular cardiac muscle cell action potential / intracellular chloride ion homeostasis / potassium ion export across plasma membrane / membrane repolarization during cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / atrial cardiac muscle cell action potential / regulation of membrane repolarization / renal sodium ion absorption / auditory receptor cell development / protein phosphatase 1 binding / detection of mechanical stimulus involved in sensory perception of sound / transporter inhibitor activity / delayed rectifier potassium channel activity / : / ventricular cardiac muscle cell action potential / potassium ion homeostasis / type 3 metabotropic glutamate receptor binding / regulation of ventricular cardiac muscle cell membrane repolarization / positive regulation of potassium ion transmembrane transport / Voltage gated Potassium channels / non-motile cilium assembly / outward rectifier potassium channel activity / intestinal absorption / cardiac muscle cell contraction / inner ear morphogenesis / adrenergic receptor signaling pathway / negative regulation of high voltage-gated calcium channel activity / response to corticosterone / renal absorption / ciliary base / protein kinase A regulatory subunit binding / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / protein kinase A catalytic subunit binding / regulation of synaptic vesicle exocytosis / presynaptic endocytosis / regulation of heart contraction / inner ear development / potassium ion import across plasma membrane / regulation of heart rate by cardiac conduction / calcineurin-mediated signaling / nitric-oxide synthase binding / regulation of cell communication by electrical coupling involved in cardiac conduction / monoatomic ion channel complex / adenylate cyclase binding / protein phosphatase activator activity / cochlea development / action potential / regulation of synaptic vesicle endocytosis / voltage-gated potassium channel activity / detection of calcium ion / social behavior / postsynaptic cytosol / regulation of cardiac muscle contraction / positive regulation of heart rate / catalytic complex / phosphatidylinositol 3-kinase binding / transport vesicle / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction / titin binding / phosphatidylinositol-4,5-bisphosphate binding / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / regulation of calcium-mediated signaling / positive regulation of cardiac muscle contraction / voltage-gated potassium channel complex / cellular response to epinephrine stimulus / calcium channel complex / substantia nigra development / potassium ion transmembrane transport / regulation of heart rate / cytoplasmic vesicle membrane / cellular response to cAMP / calyx of Held / nitric-oxide synthase regulator activity / adenylate cyclase activator activity / regulation of cytokinesis / protein serine/threonine kinase activator activity / erythrocyte differentiation / spindle microtubule / sarcomere / response to amphetamine
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 / Recoverin; domain 1 / : / EF-hand domain pair / EF-hand, calcium binding motif ...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 / Recoverin; domain 1 / : / 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 / EF-hand domain pair / Ion transport domain / Ion transport protein / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-I0S / : / Chem-PIO / Calmodulin-3 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsMa, D. / Guo, J.
Funding support China, 6items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 14, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 1
B: Calmodulin-3
C: Potassium voltage-gated channel subfamily KQT member 1
D: Calmodulin-3
E: Potassium voltage-gated channel subfamily KQT member 1
F: Calmodulin-3
G: Potassium voltage-gated channel subfamily KQT member 1
H: Calmodulin-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)389,44020
Polymers384,4118
Non-polymers5,02912
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Potassium voltage-gated channel subfamily KQT member 1 / IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1 / KQT-like 1 / Voltage- ...IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1 / KQT-like 1 / Voltage-gated potassium channel subunit Kv7.1


Mass: 76487.297 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ1, KCNA8, KCNA9, KVLQT1 / Production host: Homo sapiens (human) / References: UniProt: P51787
#2: Protein
Calmodulin-3


Mass: 19615.445 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM3, CALML2, CAM3, CAMC, CAMIII / Production host: Homo sapiens (human) / References: UniProt: P0DP25
#3: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#4: Chemical
ChemComp-I0S / (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide


Mass: 471.592 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H25N3O4S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
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 / dioctanoyl l-alpha-phosphatidyl-d-myo-inositol 4,5-diphosphate


Mass: 746.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H49O19P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: human KCNQ1-CaM-ML277-PIP2 complex in state A / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1-#2 / 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: -1300 nm / Nominal defocus min: -1100 nm
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 103745 / Symmetry type: POINT

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