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- PDB-9z4a: Cryo-EM structure of the human PRMT5:MEP50:pICln complex at a 4:3... -

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Basic information

Entry
Database: PDB / ID: 9z4a
TitleCryo-EM structure of the human PRMT5:MEP50:pICln complex at a 4:3:4 stoichiometric ratio
Components
  • Methylosome protein WDR77
  • Methylosome subunit pICln
  • Protein arginine N-methyltransferase 5, N-terminally processed
KeywordsTRANSFERASE / arginine methyltransferase
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 / histone H4R3 methyltransferase activity / protein-arginine N-methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / pICln-Sm protein complex / methylosome ...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 / histone H4R3 methyltransferase activity / protein-arginine N-methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / pICln-Sm protein complex / methylosome / 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 / positive regulation of oligodendrocyte differentiation / negative regulation of gene expression via chromosomal CpG island methylation / negative regulation of cGAS/STING signaling pathway / chloride transport / 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 / methyltransferase activity / regulation of signal transduction by p53 class mediator / circadian regulation of gene expression / DNA-templated transcription termination / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / protein polyubiquitination / RMTs methylate histone arginines / p53 binding / microtubule cytoskeleton / transcription corepressor activity / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / chromosome / 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
S-ADENOSYL-L-HOMOCYSTEINE / Protein arginine N-methyltransferase 5 / Methylosome subunit pICln / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.84 Å
AuthorsXu, X. / Chi, Z. / Jiang, W. / Li, C.
Funding support United States, 1items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein arginine N-methyltransferase 5, N-terminally processed
B: Methylosome protein WDR77
C: Methylosome subunit pICln
D: Protein arginine N-methyltransferase 5, N-terminally processed
E: Methylosome protein WDR77
F: Methylosome subunit pICln
G: Protein arginine N-methyltransferase 5, N-terminally processed
H: Methylosome protein WDR77
I: Methylosome subunit pICln
J: Protein arginine N-methyltransferase 5, N-terminally processed
L: Methylosome subunit pICln
hetero molecules


Theoretical massNumber of molelcules
Total (without water)401,26315
Polymers399,72511
Non-polymers1,5384
Water00
1


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

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Components

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


Mass: 71805.531 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O14744
#2: Protein Methylosome protein WDR77 / Androgen receptor cofactor p44 / Methylosome protein 50 / MEP-50 / WD repeat-containing protein 77 / p44/Mep50


Mass: 33014.988 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR77, MEP50, WD45, HKMT1069, Nbla10071 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BQA1
#3: Protein/peptide
Methylosome subunit pICln / Chloride channel / nucleotide sensitive 1A / Chloride conductance regulatory protein ICln / I(Cln) ...Chloride channel / nucleotide sensitive 1A / Chloride conductance regulatory protein ICln / I(Cln) / Chloride ion current inducer protein / ClCI / Reticulocyte pICln


Mass: 3364.474 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLNS1A, CLCI, ICLN / Production host: Escherichia coli (E. coli) / References: UniProt: P54105
#4: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: The PRMT5:MEP50:pICln complex at a 4:3:4 stoichiometric ratio
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 54.44 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30000 / Symmetry type: POINT
RefinementHighest resolution: 3.84 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00228041
ELECTRON MICROSCOPYf_angle_d0.48338216
ELECTRON MICROSCOPYf_dihedral_angle_d13.64710048
ELECTRON MICROSCOPYf_chiral_restr0.0434238
ELECTRON MICROSCOPYf_plane_restr0.0064954

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