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- EMDB-73799: Cryo-EM structure of the human PRMT5:MEP50:pICln complex at a 4:4... -

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Basic information

Entry
Database: EMDB / ID: EMD-73799
TitleCryo-EM structure of the human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio
Map data
Sample
  • Complex: The human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio
    • Protein or peptide: Protein arginine N-methyltransferase 5, N-terminally processed
    • Protein or peptide: Methylosome protein WDR77
    • Protein or peptide: Methylosome subunit pICln
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE
Keywordsarginine methyltransferase / TRANSFERASE
Function / homology
Function and homology information


positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / Golgi ribbon formation / peptidyl-arginine methylation / histone H4R3 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / Golgi ribbon formation / peptidyl-arginine methylation / histone H4R3 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / pICln-Sm protein complex / cell volume homeostasis / positive regulation of rRNA processing / methyl-CpG binding / endothelial cell activation / mRNA cis splicing, via spliceosome / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase activity / chloride transport / positive regulation of oligodendrocyte differentiation / negative regulation of gene expression via chromosomal CpG island methylation / E-box binding / histone methyltransferase complex / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of cell differentiation / regulation of ERK1 and ERK2 cascade / liver regeneration / ribonucleoprotein complex binding / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / spliceosomal complex / regulation of signal transduction by p53 class mediator / methyltransferase activity / circadian regulation of gene expression / DNA-templated transcription termination / Regulation of TP53 Activity through Methylation / protein polyubiquitination / RMTs methylate histone arginines / p53 binding / microtubule cytoskeleton / transcription corepressor activity / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / chromatin remodeling / protein heterodimerization activity / regulation of DNA-templated transcription / chromatin / Golgi apparatus / RNA binding / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
ICln / Protein ICln/Lot5/Saf5 / Regulator of volume decrease after cellular swelling / : / Protein arginine N-methyltransferase PRMT5 / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / PRMT5 arginine-N-methyltransferase ...ICln / Protein ICln/Lot5/Saf5 / Regulator of volume decrease after cellular swelling / : / Protein arginine N-methyltransferase PRMT5 / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 arginine-N-methyltransferase / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / PH-like domain superfamily / WD domain, G-beta repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Protein arginine N-methyltransferase 5 / Methylosome subunit pICln / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsXu X / Chi Z / Jiang W / Li C
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA212403 United States
CitationJournal: J Enzyme Inhib Med Chem / Year: 2026
Title: Cryo-EM structure-based discovery of etravirine as a specific inhibitor of PRMT5/pICln protein-protein interaction for prostate cancer treatment.
Authors: Zhixia Chi / Xueyong Xu / Zhihang Shen / Xuehong Deng / Bennett D Elzey / Chenglong Li / Wen Jiang / Chang-Deng Hu /
Abstract: Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancers and correlates with poor patient survival. In prostate cancer, PRMT5 cooperates with its cofactor pICln to promote tumour ...Protein arginine methyltransferase 5 (PRMT5) is overexpressed in many cancers and correlates with poor patient survival. In prostate cancer, PRMT5 cooperates with its cofactor pICln to promote tumour growth by epigenetically activating androgen receptor (AR) expression. Using a near-atomic cryo-EM structure of PRMT5/MEP50/pICln complex, we identified a previously undefined, pICln-specific protein-protein interaction (PPI) interface on PRMT5, termed P4I. Structure-based virtual screening identified the FDA-approved compound etravirine as a binder to this site. BiFC, Co-IP, and PLA assays confirmed that etravirine disrupts PRMT5/pICln interaction. A cryo-EM structure of PRMT5/MEP50/etravirine further validated on-target binding at P4I. Functionally, etravirine reduced prostate cancer cell proliferation, inhibited tumour growth, and downregulated AR and AR-V7 expression in cells and in mouse models. These results demonstrate that the unique P4I interface is a promising therapeutic target and that etravirine serves as a proof-of-concept lead compound for exploring the potential of P4I-targeted strategies in prostate cancer.
History
DepositionNov 9, 2025-
Header (metadata) releaseSep 16, 2026-
Map releaseSep 16, 2026-
UpdateSep 16, 2026-
Current statusSep 16, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73799.png

Downloads & links

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Map

FileDownload / File: emd_73799.map.gz / Format: CCP4 / Size: 600.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 540 pix.
= 471.96 Å		0.87 Å/pix.
x 540 pix.
= 471.96 Å		0.87 Å/pix.
x 540 pix.
= 471.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.874 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.32
Minimum - Maximum-1.4307702 - 2.3447833
Average (Standard dev.)-0.00014337983 (±0.051532928)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions540540540
Spacing540540540
CellA=B=C: 471.96002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_73799_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_73799_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : The human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio

EntireName: The human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio
Components
  • Complex: The human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio
    • Protein or peptide: Protein arginine N-methyltransferase 5, N-terminally processed
    • Protein or peptide: Methylosome protein WDR77
    • Protein or peptide: Methylosome subunit pICln
  • Ligand: S-ADENOSYL-L-HOMOCYSTEINE

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Supramolecule #1: The human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio

SupramoleculeName: The human PRMT5:MEP50:pICln complex at a 4:4:4 stoichiometric ratio
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein arginine N-methyltransferase 5, N-terminally processed

MacromoleculeName: Protein arginine N-methyltransferase 5, N-terminally processed
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.805531 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: RVSSGRDLNC VPEIADTLGA VAKQGFDFLC MPVFHPRFKR EFIQEPAKNR PGPQTRSDLL LSGRDWNTLI VGKLSPWIRP DSKVEKIRR NSEAAMLQEL NFGAYLGLPA FLLPLNQEDN TNLARVLTNH IHTGHHSSMF WMRVPLVAPE DLRDDIIENA P TTHTEEYS ...String:
RVSSGRDLNC VPEIADTLGA VAKQGFDFLC MPVFHPRFKR EFIQEPAKNR PGPQTRSDLL LSGRDWNTLI VGKLSPWIRP DSKVEKIRR NSEAAMLQEL NFGAYLGLPA FLLPLNQEDN TNLARVLTNH IHTGHHSSMF WMRVPLVAPE DLRDDIIENA P TTHTEEYS GEEKTWMWWH NFRTLCDYSK RIAVALEIGA DLPSNHVIDR WLGEPIKAAI LPTSIFLTNK KGFPVLSKMH QR LIFRLLK LEVQFIITGT NHHSEKEFCS YLQYLEYLSQ NRPPPNAYEL FAKGYEDYLQ SPLQPLMDNL ESQTYEVFEK DPI KYSQYQ QAIYKCLLDR VPEEEKDTNV QVLMVLGAGR GPLVNASLRA AKQADRRIKL YAVEKNPNAV VTLENWQFEE WGSQ VTVVS SDMREWVAPE KADIIVSELL GSFADNELSP ECLDGAQHFL KDDGVSIPGE YTSFLAPISS SKLYNEVRAC REKDR DPEA QFEMPYVVRL HNFHQLSAPQ PCFTFSHPNR DPMIDNNRYC TLEFPVEVNT VLHGFAGYFE TVLYQDITLS IRPETH SPG MFSWFPILFP IKQPITVREG QTICVRFWRC SNSKKVWYEW AVTAPVCSAI HNPTGRSYTI GL

UniProtKB: Protein arginine N-methyltransferase 5

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Macromolecule #2: Methylosome protein WDR77

MacromoleculeName: Methylosome protein WDR77 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.014988 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: APACMERQLE AARYRSDGAL LLGASSLSGR CWAGSLWLFK DPCAAPNEGF CSAGVQTEAG VADLTWVGER GILVASDSGA VELWELDEN ETLIVSKFCK YEHDDIVSTV SVLSSGTQAV SGSKDICIKV WDLAQQVVLS SYRAHAAQVT CVAASPHKDS V FLSCSEDN ...String:
APACMERQLE AARYRSDGAL LLGASSLSGR CWAGSLWLFK DPCAAPNEGF CSAGVQTEAG VADLTWVGER GILVASDSGA VELWELDEN ETLIVSKFCK YEHDDIVSTV SVLSSGTQAV SGSKDICIKV WDLAQQVVLS SYRAHAAQVT CVAASPHKDS V FLSCSEDN RILLWDTRCP KPASQIGCSA PGYLPTSLAW HPQQSEVFVF GDENGTVSLV DTKSTSCVLS SAVHSQCVTG LV FSPHSVP FLASLSEDCS LAVLDSSLSE LFRSQAHRDF VRDATWSPLN HSLLTTVGWD HQVVHHVVPT

UniProtKB: Methylosome protein WDR77

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Macromolecule #3: Methylosome subunit pICln

MacromoleculeName: Methylosome subunit pICln / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.364474 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
VRTEDSIRDY EDGMEVDTTP TVAGQFEDAD

UniProtKB: Methylosome subunit pICln

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Macromolecule #4: S-ADENOSYL-L-HOMOCYSTEINE

MacromoleculeName: S-ADENOSYL-L-HOMOCYSTEINE / type: ligand / ID: 4 / Number of copies: 4 / Formula: SAH
Molecular weightTheoretical: 384.411 Da
Chemical component information

ChemComp-SAH:
S-ADENOSYL-L-HOMOCYSTEINE

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 54.44 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4gqb

Final reconstructionAlgorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 100000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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