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- PDB-9lw1: TMEM164-substrate -

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Basic information

Entry
Database: PDB / ID: 9lw1
TitleTMEM164-substrate
ComponentsTransmembrane protein 164
KeywordsMEMBRANE PROTEIN / TMEM164
Function / homologyTransmembrane protein 164 / TMEM164 family / positive regulation of ferroptosis / membrane / Petroselinic acid / CHOLESTEROL / [1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE / Transmembrane protein 164
Function and homology information
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsZhang, M.F.
Funding support1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 7, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 7, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transmembrane protein 164
B: Transmembrane protein 164
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,87122
Polymers67,0752
Non-polymers5,79620
Water724
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Transmembrane protein 164 / Arachidonoyl ether phospholipid synthase


Mass: 33537.695 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM164 / Production host: Homo sapiens (human) / References: UniProt: Q5U3C3

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Non-polymers , 5 types, 24 molecules

#2: Chemical ChemComp-LPC / [1-MYRISTOYL-GLYCEROL-3-YL]PHOSPHONYLCHOLINE


Mass: 468.585 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H47NO7P / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-4I1 / Petroselinic acid


Mass: 282.461 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: C18H34O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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Details

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: TMEM164 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: Tecnai F30 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F30
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 2000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45000 / Symmetry type: POINT

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