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- EMDB-63426: TMEM164-substrate -

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Basic information

Entry
Database: EMDB / ID: EMD-63426
TitleTMEM164-substrate
Map data
Sample
  • Complex: TMEM164
    • Protein or peptide: Transmembrane protein 164
  • Ligand: [1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL
  • Ligand: Petroselinic acid
  • Ligand: water
KeywordsTMEM164 / MEMBRANE PROTEIN
Function / homologyTransmembrane protein 164 / TMEM164 family / positive regulation of ferroptosis / membrane / Transmembrane protein 164
Function and homology information
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsZhang MF
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM structure of TMEM164 reveals distinct phospholipid remodeling mechanisms with anti-ferroptotic potential.
Authors: Minjing Ke / Yuanyue Shan / Ziwei Zhai / Guoqiang Yao / Xinyi Guo / Xiaoxi Li / Zichao Wu / Huifeng Chen / Mengmeng Zhang / Meiyu Chen / Ying Li / Chengchen Zhao / Bo Wang / Micky D ...Authors: Minjing Ke / Yuanyue Shan / Ziwei Zhai / Guoqiang Yao / Xinyi Guo / Xiaoxi Li / Zichao Wu / Huifeng Chen / Mengmeng Zhang / Meiyu Chen / Ying Li / Chengchen Zhao / Bo Wang / Micky D Tortorella / Xiaodong Shu / Mingfeng Zhang / Junqi Kuang / Duanqing Pei /
Abstract: Phospholipids in cell membrane provide both regulatory and structural function of a cell. How lipid remodeling regulates cell fate remains less explored. Here we report the cryo-electron microscopy ...Phospholipids in cell membrane provide both regulatory and structural function of a cell. How lipid remodeling regulates cell fate remains less explored. Here we report the cryo-electron microscopy structure of TMEM164 identified by genome-wide CRISPR screen as an anti-ferroptotic factor. The overall architecture reveals a dimer of two 7 transmembrane domain monomers and a metal ion catalytic center with phospholipid substrate in a distinct polyunsaturated fatty acyl (PUFA)-C123 intermediate state. Both loss and gain of its function result in the decline of PUFA-ePE and elevation of C16/18:1-ePE, consequently confer resistance to GPX4 inhibitor RSL3 induced ferroptosis. Mutagenesis studies further validate critical residues for the catalytic center (C123) and the chelates center (E106, Y177 and H181). Through virtual screen and rational design, we identify and test candidate inhibitors for TMEM164, including activity for Montelukast S-enantiomer with 4 order of magnitude higher affinity. Our works not only demonstrates TMEM164 as a membrane lipid remodeler that controls the ferroptotic fate, but also highlights the power of integrating multi-scale platforms to unravel distinct mechanisms and functions.
History
DepositionFeb 13, 2025-
Header (metadata) releaseJan 7, 2026-
Map releaseJan 7, 2026-
UpdateJan 7, 2026-
Current statusJan 7, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63426.png

Downloads & links

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Map

FileDownload / File: emd_63426.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.57 Å/pix.
x 512 pix.
= 291.84 Å		0.57 Å/pix.
x 512 pix.
= 291.84 Å		0.57 Å/pix.
x 512 pix.
= 291.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.57 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.4552911 - 0.68475544
Average (Standard dev.)0.000041102772 (±0.01268478)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 291.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_63426_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_63426_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : TMEM164

EntireName: TMEM164
Components
  • Complex: TMEM164
    • Protein or peptide: Transmembrane protein 164
  • Ligand: [1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL
  • Ligand: Petroselinic acid
  • Ligand: water

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Supramolecule #1: TMEM164

SupramoleculeName: TMEM164 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transmembrane protein 164

MacromoleculeName: Transmembrane protein 164 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.537695 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSRYSYQSLL DWLYGGVDPS FAGNGGPDCA AFLSWQQRLL ESVVVLTLAL LEILVALRHI LRQTKEDGRG SPGSQPEQVT QRPEEGKES LSKNLLLVAL CLTFGVEVGF KFATKTVIYL LNPCHLVTMM HIFLLACPPC RGAIVVFKLQ MHMLNGALLA L LFPVVNTR ...String:
MSRYSYQSLL DWLYGGVDPS FAGNGGPDCA AFLSWQQRLL ESVVVLTLAL LEILVALRHI LRQTKEDGRG SPGSQPEQVT QRPEEGKES LSKNLLLVAL CLTFGVEVGF KFATKTVIYL LNPCHLVTMM HIFLLACPPC RGAIVVFKLQ MHMLNGALLA L LFPVVNTR LLPFELEIYY IQHVMLYVVP IYLLWKGGAY TPEPLSSFRW ALLSTGLMFF YHFSVLQILG LVTEVNLNNM LC PAISDPF YGPWYRIWAS GHQTLMTMTH GKLVILFSYM AGPLCKYLLD LLRLPAKKID

UniProtKB: Transmembrane protein 164

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Macromolecule #2: [1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE

MacromoleculeName: [1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE / type: ligand / ID: 2 / Number of copies: 2 / Formula: LPC
Molecular weightTheoretical: 468.585 Da
Chemical component information

ChemComp-LPC:
[1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #5: Petroselinic acid

MacromoleculeName: Petroselinic acid / type: ligand / ID: 5 / Number of copies: 14 / Formula: 4I1
Molecular weightTheoretical: 282.461 Da
Chemical component information

ChemComp-4I1:
Petroselinic acid

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI F30
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 2.0 µm
Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 45000
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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