+Open data
-Basic information
Entry | Database: PDB / ID: 8j05 | |||||||||||||||
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Title | Human KCNQ2-CaM complex in the presence of PIP2 | |||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / potassium voltage-gated channel / PIP2 | |||||||||||||||
Function / homology | Function and homology information axon initial segment / Voltage gated Potassium channels / node of Ranvier / CaM pathway / Interaction between L1 and Ankyrins / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde ...axon initial segment / Voltage gated Potassium channels / node of Ranvier / CaM pathway / Interaction between L1 and Ankyrins / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / ankyrin binding / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / positive regulation of cyclic-nucleotide phosphodiesterase activity / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / regulation of cardiac muscle cell action potential / Activation of RAC1 downstream of NMDARs / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / Phase 0 - rapid depolarisation / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / voltage-gated potassium channel activity / action potential / RHO GTPases activate PAKs / : / Ion transport by P-type ATPases / Long-term potentiation / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / DARPP-32 events / detection of calcium ion / regulation of cardiac muscle contraction / regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / cellular response to interferon-beta / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium channel inhibitor activity / Protein methylation / eNOS activation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Activation of AMPK downstream of NMDARs / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / : / Ion homeostasis / titin binding / regulation of calcium-mediated signaling / positive regulation of protein autophosphorylation / voltage-gated potassium channel complex / sperm midpiece / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / sarcomere / FCERI mediated Ca+2 mobilization / protein serine/threonine kinase activator activity / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / response to calcium ion / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / cellular response to type II interferon / G2/M transition of mitotic cell cycle / spindle pole / RAS processing / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / calcium-dependent protein binding / Inactivation, recovery and regulation of the phototransduction cascade / Signaling by BRAF and RAF1 fusions Similarity search - Function | |||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||||||||
Authors | Ma, D. / Li, X. / Guo, J. | |||||||||||||||
Funding support | China, 4items
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Citation | Journal: Nat Commun / Year: 2023 Title: Ligand activation mechanisms of human KCNQ2 channel. Authors: Demin Ma / Yueming Zheng / Xiaoxiao Li / Xiaoyu Zhou / Zhenni Yang / Yan Zhang / Long Wang / Wenbo Zhang / Jiajia Fang / Guohua Zhao / Panpan Hou / Fajun Nan / Wei Yang / Nannan Su / ...Authors: Demin Ma / Yueming Zheng / Xiaoxiao Li / Xiaoyu Zhou / Zhenni Yang / Yan Zhang / Long Wang / Wenbo Zhang / Jiajia Fang / Guohua Zhao / Panpan Hou / Fajun Nan / Wei Yang / Nannan Su / Zhaobing Gao / Jiangtao Guo / Abstract: The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but ...The human voltage-gated potassium channel KCNQ2/KCNQ3 carries the neuronal M-current, which helps to stabilize the membrane potential. KCNQ2 can be activated by analgesics and antiepileptic drugs but their activation mechanisms remain unclear. Here we report cryo-electron microscopy (cryo-EM) structures of human KCNQ2-CaM in complex with three activators, namely the antiepileptic drug cannabidiol (CBD), the lipid phosphatidylinositol 4,5-bisphosphate (PIP), and HN37 (pynegabine), an antiepileptic drug in the clinical trial, in an either closed or open conformation. The activator-bound structures, along with electrophysiology analyses, reveal the binding modes of two CBD, one PIP, and two HN37 molecules in each KCNQ2 subunit, and elucidate their activation mechanisms on the KCNQ2 channel. These structures may guide the development of antiepileptic drugs and analgesics that target KCNQ2. | |||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8j05.cif.gz | 748 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8j05.ent.gz | 620.4 KB | Display | PDB format |
PDBx/mmJSON format | 8j05.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8j05_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8j05_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 8j05_validation.xml.gz | 57.4 KB | Display | |
Data in CIF | 8j05_validation.cif.gz | 86.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/j0/8j05 ftp://data.pdbj.org/pub/pdb/validation_reports/j0/8j05 | HTTPS FTP |
-Related structure data
Related structure data | 35884MC 8izyC 8j00C 8j01C 8j02C 8j03C 8j04C 8w4uC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 73627.812 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ2 / Production host: Homo sapiens (human) / References: UniProt: O43526 #2: Protein | Mass: 19615.445 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23 |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Human KCNQ2-CaM complex in the presence of PIP2 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118013 / Symmetry type: POINT |