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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 / 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 / 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 / Ion transport domain / Ion transport protein / EF-hand domain pair / 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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