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- PDB-9ovy: Cryo-EM structure of human PRMT5:MEP50 in complex with SAH and co... -

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Basic information

Entry
Database: PDB / ID: 9ovy
TitleCryo-EM structure of human PRMT5:MEP50 in complex with SAH and compounds 16-19F and HJL-1
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
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 / methylosome / positive regulation of rRNA processing ...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 / methylosome / positive regulation of rRNA processing / methyl-CpG binding / endothelial cell activation / 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 / 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 / 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 / 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 / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / 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. ...: / 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. / 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
Chem-65B / : / S-ADENOSYL-L-HOMOCYSTEINE / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 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
DepositionJun 1, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 2.0Sep 16, 2026Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / em_admin / entity / pdbx_entity_nonpoly
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Revision 1.1Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / EM metadata
Group: Database references / Experimental summary / Structure summary
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Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _entity.pdbx_description

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
G: Protein arginine N-methyltransferase 5
E: Protein arginine N-methyltransferase 5
F: Methylosome protein 50
C: Protein arginine N-methyltransferase 5
D: Methylosome protein 50
hetero molecules


Theoretical massNumber of molelcules
Total (without water)406,03219
Polymers401,3387
Non-polymers4,69412
Water00
1


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

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Components

#1: Protein
Protein arginine N-methyltransferase 5 / 72 kDa ICln-binding protein / Histone-arginine N-methyltransferase PRMT5 / Jak-binding protein 1 / ...72 kDa ICln-binding protein / Histone-arginine N-methyltransferase PRMT5 / Jak-binding protein 1 / Shk1 kinase-binding protein 1 homolog / SKB1Hs


Mass: 72766.664 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, type II protein arginine methyltransferase
#2: Protein Methylosome protein 50 / MEP-50 / Androgen receptor cofactor p44 / WD repeat-containing protein 77 / p44/Mep50


Mass: 36757.246 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: Chemical
ChemComp-65B / Etravirine / Etravine / 4-({6-AMINO-5-BROMO-2-[(4-CYANOPHENYL)AMINO]PYRIMIDIN-4-YL}OXY)-3,5-DIMETHYLBENZONITRILE


Mass: 435.277 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H15BrN6O
#4: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20N6O5S
#5: Chemical
ChemComp-A1CEU / 8-chloro-1-[(2,4-diaminoquinazolin-7-yl)methyl]-3,4-dihydroquinolin-2(1H)-one


Mass: 353.806 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H16ClN5O
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: Cryo-EM structure of human PRMT5:MEP50 in complex with SAH and compounds 16-19F and HJL-1
Type: COMPLEX / Entity ID: #1-#2 / 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 100000 / Algorithm: FOURIER SPACE / Symmetry type: POINT
RefinementHighest resolution: 3.1 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00227814
ELECTRON MICROSCOPYf_angle_d0.47537890
ELECTRON MICROSCOPYf_dihedral_angle_d5.4873680
ELECTRON MICROSCOPYf_chiral_restr0.0424122
ELECTRON MICROSCOPYf_plane_restr0.0044884

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