+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-35195 | |||||||||
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Title | Rat Kir4.1 in complex with PIP2 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | kir4.1 / ion channel / transport protein / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information glutamate reuptake / Potassium transport channels / L-glutamate import / response to blue light / response to mineralocorticoid / central nervous system myelination / regulation of resting membrane potential / cellular response to potassium ion / oligodendrocyte development / astrocyte projection ...glutamate reuptake / Potassium transport channels / L-glutamate import / response to blue light / response to mineralocorticoid / central nervous system myelination / regulation of resting membrane potential / cellular response to potassium ion / oligodendrocyte development / astrocyte projection / inward rectifier potassium channel activity / potassium ion homeostasis / non-motile cilium assembly / membrane hyperpolarization / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / regulation of monoatomic ion transmembrane transport / adult walking behavior / monoatomic ion channel complex / ciliary base / optic nerve development / potassium ion import across plasma membrane / microvillus / potassium channel activity / response to glucocorticoid / potassium ion transmembrane transport / visual perception / regulation of membrane potential / establishment of localization in cell / regulation of long-term neuronal synaptic plasticity / potassium ion transport / presynapse / cell body / basolateral plasma membrane / apical plasma membrane / signaling receptor binding / ATP binding / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Rattus norvegicus (Norway rat) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.85 Å | |||||||||
Authors | Zhao C / Guo J | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nat Chem Biol / Year: 2024 Title: Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses. Authors: Xiaoyu Zhou / Cheng Zhao / Haiyan Xu / Yixiang Xu / Li Zhan / Pei Wang / Jingyi He / Taotao Lu / Yueling Gu / Yan Yang / Chanjuan Xu / Yiyang Chen / Yuxuan Liu / Yue Zeng / Fuyun Tian / Qian ...Authors: Xiaoyu Zhou / Cheng Zhao / Haiyan Xu / Yixiang Xu / Li Zhan / Pei Wang / Jingyi He / Taotao Lu / Yueling Gu / Yan Yang / Chanjuan Xu / Yiyang Chen / Yuxuan Liu / Yue Zeng / Fuyun Tian / Qian Chen / Xin Xie / Jianfeng Liu / Hailan Hu / Jian Li / Yueming Zheng / Jiangtao Guo / Zhaobing Gao / Abstract: Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying ...Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_35195.map.gz | 17.2 MB | EMDB map data format | |
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Header (meta data) | emd-35195-v30.xml emd-35195.xml | 14.7 KB 14.7 KB | Display Display | EMDB header |
Images | emd_35195.png | 115.6 KB | ||
Filedesc metadata | emd-35195.cif.gz | 5.7 KB | ||
Others | emd_35195_half_map_1.map.gz emd_35195_half_map_2.map.gz | 17.1 MB 16.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-35195 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35195 | HTTPS FTP |
-Validation report
Summary document | emd_35195_validation.pdf.gz | 853.6 KB | Display | EMDB validaton report |
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Full document | emd_35195_full_validation.pdf.gz | 853.1 KB | Display | |
Data in XML | emd_35195_validation.xml.gz | 10.1 KB | Display | |
Data in CIF | emd_35195_validation.cif.gz | 11.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35195 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35195 | HTTPS FTP |
-Related structure data
Related structure data | 8i5mMC 8i5nC 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_35195.map.gz / Format: CCP4 / Size: 22.2 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 |
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Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_35195_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Rat Kir4.1 in complex with PIP2
Entire | Name: Rat Kir4.1 in complex with PIP2 |
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Components |
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-Supramolecule #1: Rat Kir4.1 in complex with PIP2
Supramolecule | Name: Rat Kir4.1 in complex with PIP2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
-Macromolecule #1: ATP-sensitive inward rectifier potassium channel 10
Macromolecule | Name: ATP-sensitive inward rectifier potassium channel 10 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 38.791723 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: GAPGIRRRRV LTKDGRSNVR MEHIADKRFL YLKDLWTTFI DMQWRYKLLL FSATFAGTWF LFGVVWYLVA VAHGDLLELG PPANHTPCV VQVHTLTGAF LFSLESQTTI GYGFRYISEE CPLAIVLLIA QLVLTTILEI FITGTFLAKI ARPKKRAETI R FSQHAVVA ...String: GAPGIRRRRV LTKDGRSNVR MEHIADKRFL YLKDLWTTFI DMQWRYKLLL FSATFAGTWF LFGVVWYLVA VAHGDLLELG PPANHTPCV VQVHTLTGAF LFSLESQTTI GYGFRYISEE CPLAIVLLIA QLVLTTILEI FITGTFLAKI ARPKKRAETI R FSQHAVVA YHNGKLCLMI RVANMRKSLL IGCQVTGKLL QTHQTKEGEN IRLNQVNVTF QVDTASDSPF LILPLTFYHV VD ETSPLKD LPLRSGEGDF ELVLILSGTV ESTSATCQVR TSYLPEEILW GYEFTPAISL SASGKYVADF SLFDQVVKVA SPG GLRDST VRYGDPEKLK LDYKDDDDK UniProtKB: ATP-sensitive inward rectifier potassium channel 10 |
-Macromolecule #2: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...
Macromolecule | Name: [(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 type: ligand / ID: 2 / Number of copies: 4 / Formula: PIO |
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Molecular weight | Theoretical: 746.566 Da |
Chemical component information | ChemComp-PIO: |
-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: 62.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 1.2 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: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 22786 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |