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- PDB-7bym: Cryo-EM structure of human KCNQ4 with retigabine -

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Basic information

Entry
Database: PDB / ID: 7bym
TitleCryo-EM structure of human KCNQ4 with retigabine
Components
  • Calmodulin-3
  • Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
KeywordsMEMBRANE PROTEIN / KCNQ / Channel / Calmodulin / PIP2 / retigabine
Function / homology
Function and homology information


transporter inhibitor activity / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / inner ear morphogenesis / negative regulation of high voltage-gated calcium channel activity / response to corticosterone / negative regulation of calcium ion export across plasma membrane ...transporter inhibitor activity / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / inner ear morphogenesis / negative regulation of high voltage-gated calcium channel activity / response to corticosterone / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / nitric-oxide synthase binding / presynaptic endocytosis / regulation of cell communication by electrical coupling involved in cardiac conduction / calcineurin-mediated signaling / regulation of synaptic vesicle exocytosis / protein phosphatase activator activity / adenylate cyclase binding / voltage-gated potassium channel activity / catalytic complex / regulation of synaptic vesicle endocytosis / detection of calcium ion / postsynaptic cytosol / potassium channel activity / regulation of cardiac muscle contraction / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / phosphatidylinositol 3-kinase binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / voltage-gated potassium channel complex / regulation of calcium-mediated signaling / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / calcium channel regulator activity / response to amphetamine / nitric-oxide synthase regulator activity / regulation of heart rate / adenylate cyclase activator activity / calyx of Held / basal plasma membrane / bioluminescence / protein serine/threonine kinase activator activity / sarcomere / regulation of cytokinesis / generation of precursor metabolites and energy / spindle microtubule / sensory perception of sound / mitochondrial membrane / potassium ion transport / Schaffer collateral - CA1 synapse / long-term synaptic potentiation / response to calcium ion / spindle pole / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / synaptic vesicle membrane / myelin sheath / growth cone / vesicle / transmembrane transporter binding / G protein-coupled receptor signaling pathway / protein domain specific binding / centrosome / calcium ion binding / protein kinase binding / protein-containing complex / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / EF-hand / : / Green fluorescent protein, GFP / Recoverin; domain 1 / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein ...Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / EF-hand / : / Green fluorescent protein, GFP / Recoverin; domain 1 / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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-FBX / : / Chem-PT5 / Calmodulin-3 / Green fluorescent protein / Potassium voltage-gated channel subfamily KQT member 4
Similarity search - Component
Biological speciesAequorea victoria (jellyfish)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsShen, H. / Li, T. / Yue, Z.
CitationJournal: Mol Cell / Year: 2021
Title: Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs.
Authors: Tian Li / Kun Wu / Zhenlei Yue / Yifei Wang / Fan Zhang / Huaizong Shen /
Abstract: Among the five KCNQ channels, also known as the K7 voltage-gated potassium (K) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological ...Among the five KCNQ channels, also known as the K7 voltage-gated potassium (K) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 Å, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels.
History
DepositionApr 23, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
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Structure visualization

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Assembly

Deposited unit
A: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
C: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
E: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
G: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
B: Calmodulin-3
D: Calmodulin-3
F: Calmodulin-3
H: Calmodulin-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)510,24019
Polymers504,7228
Non-polymers5,51911
Water724
1


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

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Components

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Protein , 2 types, 8 molecules ACEGBDFH

#1: Protein
Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4 / KQT-like 4 / Potassium channel subunit alpha KvLQT4 / Voltage-gated potassium channel subunit Kv7.4


Mass: 109327.836 Da / Num. of mol.: 4 / Mutation: F64L/S65T/K107T/A206K/H231L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Aequorea victoria (jellyfish), (gene. exp.) Homo sapiens (human)
Gene: GFP, KCNQ4 / Production host: Homo sapiens (human) / References: UniProt: P42212, UniProt: P56696
#2: Protein
Calmodulin-3


Mass: 16852.545 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

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Non-polymers , 4 types, 15 molecules

#3: Chemical
ChemComp-PT5 / [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate / Phosphatidylinositol 4,5-bisphosphate / PtdIns(4,5)P2


Mass: 1047.088 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C47H85O19P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#4: Chemical
ChemComp-FBX / ethyl N-[2-azanyl-4-[(4-fluorophenyl)methylamino]phenyl]carbamate / Retigabine, Ezogabine


Mass: 303.331 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18FN3O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: K
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: Complex of human KCNQ4 and retigabine / Type: COMPLEX / 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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 278944 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048536
ELECTRON MICROSCOPYf_angle_d0.57911564
ELECTRON MICROSCOPYf_dihedral_angle_d25.2231152
ELECTRON MICROSCOPYf_chiral_restr0.0321272
ELECTRON MICROSCOPYf_plane_restr0.0021404

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