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- PDB-8i5n: Rat Kir4.1 in complex with PIP2 and Lys05 -

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Basic information

Entry
Database: PDB / ID: 8i5n
TitleRat Kir4.1 in complex with PIP2 and Lys05
ComponentsATP-sensitive inward rectifier potassium channel 10
KeywordsMEMBRANE PROTEIN / kir4.1 / ion channel / transport protein
Function / homology
Function and homology information


glutamate reuptake / Potassium transport channels / L-glutamate import / central nervous system myelination / response to blue light / regulation of resting membrane potential / regulation of monoatomic ion transmembrane transport / inward rectifier potassium channel activity / potassium ion homeostasis / optic nerve development ...glutamate reuptake / Potassium transport channels / L-glutamate import / central nervous system myelination / response to blue light / regulation of resting membrane potential / regulation of monoatomic ion transmembrane transport / inward rectifier potassium channel activity / potassium ion homeostasis / optic nerve development / non-motile cilium assembly / oligodendrocyte development / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cellular response to potassium ion / membrane hyperpolarization / adult walking behavior / response to mineralocorticoid / astrocyte projection / ciliary base / microvillus / potassium ion import across plasma membrane / monoatomic ion channel complex / potassium channel activity / potassium ion transmembrane transport / visual perception / response to glucocorticoid / 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
Potassium channel, inwardly rectifying, Kir1.2 / Potassium channel, inwardly rectifying, transmembrane domain / Inward rectifier potassium channel transmembrane domain / Potassium channel, inwardly rectifying, Kir, cytoplasmic / Potassium channel, inwardly rectifying, Kir / Inward rectifier potassium channel, C-terminal / Inward rectifier potassium channel C-terminal domain / Immunoglobulin E-set
Similarity search - Domain/homology
Chem-PIO / ATP-sensitive inward rectifier potassium channel 10
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsZhao, C. / Guo, J.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Education (MoE, China)Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University China
CitationJournal: 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
DepositionJan 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.0Feb 28, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0Feb 28, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 28, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ATP-sensitive inward rectifier potassium channel 10
B: ATP-sensitive inward rectifier potassium channel 10
C: ATP-sensitive inward rectifier potassium channel 10
D: ATP-sensitive inward rectifier potassium channel 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,1538
Polymers155,1674
Non-polymers2,9864
Water00
1


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

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Components

#1: Protein
ATP-sensitive inward rectifier potassium channel 10 / ATP-sensitive inward rectifier potassium channel KAB-2 / BIR10 / Brain-specific inwardly rectifying ...ATP-sensitive inward rectifier potassium channel KAB-2 / BIR10 / Brain-specific inwardly rectifying K(+) channel 1 / BIRK1 / Inward rectifier K(+) channel Kir4.1 / Potassium channel / inwardly rectifying subfamily J member 10


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 (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P49655
#2: 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
Has protein modificationY

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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: Rat Kir4.1 in complex with PIP2 and Lys05 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
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: DARK FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 62 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75833 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00920396
ELECTRON MICROSCOPYf_angle_d1.34636912
ELECTRON MICROSCOPYf_dihedral_angle_d12.5258148
ELECTRON MICROSCOPYf_chiral_restr0.0811652
ELECTRON MICROSCOPYf_plane_restr0.0042900

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