+Open data
-Basic information
Entry | Database: PDB / ID: 8i5m | ||||||
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Title | Rat Kir4.1 in complex with PIP2 | ||||||
Components | ATP-sensitive inward rectifier potassium channel 10 | ||||||
Keywords | MEMBRANE PROTEIN / kir4.1 / ion channel / transport 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 | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å | ||||||
Authors | Zhao, C. / Guo, J. | ||||||
Funding support | China, 1items
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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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8i5m.cif.gz | 421.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8i5m.ent.gz | 350.1 KB | Display | PDB format |
PDBx/mmJSON format | 8i5m.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8i5m_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8i5m_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8i5m_validation.xml.gz | 44.7 KB | Display | |
Data in CIF | 8i5m_validation.cif.gz | 55.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/i5/8i5m ftp://data.pdbj.org/pub/pdb/validation_reports/i5/8i5m | HTTPS FTP |
-Related structure data
Related structure data | 35195MC 8i5nC 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: 38791.723 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Kcnj10, Kab-2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P49655 #2: Chemical | ChemComp-PIO / [( Has ligand of interest | Y | Has protein modification | Y | |
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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: Rat Kir4.1 in complex with PIP2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
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: DARK FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 62 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 22786 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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