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- PDB-9dod: Crystal structure of PRMT5:MEP50 in complex with PRT543 -

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Basic information

Entry
Database: PDB / ID: 9dod
TitleCrystal structure of PRMT5:MEP50 in complex with PRT543
Components
  • Methylosome protein WDR77
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / PRMT5 / MEP50 / inhibitor / protein-ligand complex
Function / homology
Function and homology information


positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / peptidyl-arginine methylation / Golgi ribbon formation / negative regulation of epithelial cell proliferation involved in prostate gland development / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / histone arginine N-methyltransferase activity ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / peptidyl-arginine methylation / Golgi ribbon formation / negative regulation of epithelial cell proliferation involved in prostate gland development / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / histone arginine N-methyltransferase activity / epithelial cell proliferation involved in prostate gland development / histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / histone H3R8 methyltransferase activity / histone H3R26 methyltransferase activity / histone H3K37 methyltransferase activity / histone H4R3 methyltransferase activity / histone H4K12 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / histone H2AQ104 methyltransferase activity / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of gene expression via chromosomal CpG island methylation / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / liver regeneration / 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 / RMTs methylate histone arginines / protein polyubiquitination / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / chromatin remodeling / protein heterodimerization activity / positive regulation of cell population proliferation / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / 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. / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / 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 protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsLeal, R.A. / Pitis, P.M. / Dou, Y. / Lin, H. / Wang, M. / Xu, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Leukemia / Year: 2025
Title: Phase Ib study of PRT543, an oral protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced splicing factor-mutant myeloid malignancies.
Authors: Bewersdorf, J.P. / Mi, X. / Lu, B. / Kuykendall, A. / Sallman, D. / Patel, M. / Stevens, D. / Philipovskiy, A. / Sutamtewagul, G. / Masarova, L. / Keiffer, G. / Verma, A. / Bhagwat, N. / ...Authors: Bewersdorf, J.P. / Mi, X. / Lu, B. / Kuykendall, A. / Sallman, D. / Patel, M. / Stevens, D. / Philipovskiy, A. / Sutamtewagul, G. / Masarova, L. / Keiffer, G. / Verma, A. / Bhagwat, N. / Wang, M. / Moore, A. / Rager, J. / Heiser, D. / Ro, S. / Hong, W.J. / Abdel-Wahab, O. / Stein, E.M.
History
DepositionSep 18, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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 WDR77
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,9357
Polymers109,2622
Non-polymers6745
Water4,792266
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5770 Å2
ΔGint-5 kcal/mol
Surface area38070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.567, 139.202, 178.548
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-1003-

HOH

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Components

#1: Protein Protein arginine N-methyltransferase 5 / PRMT5 / 72 kDa ICln-binding protein / Histone-arginine N-methyltransferase PRMT5 / Jak-binding ...PRMT5 / 72 kDa ICln-binding protein / Histone-arginine N-methyltransferase PRMT5 / Jak-binding protein 1 / Shk1 kinase-binding protein 1 homolog / SKB1 homolog / SKB1Hs


Mass: 72635.461 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: O14744, type II protein arginine methyltransferase
#2: Protein Methylosome protein WDR77 / Androgen receptor cofactor p44 / Methylosome protein 50 / MEP-50 / WD repeat-containing protein 77 / p44/Mep50


Mass: 36626.051 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR77, MEP50, WD45, HKMT1069, Nbla10071 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q9BQA1
#3: Chemical ChemComp-A1A79 / 7-[(3xi,5R)-5-C-(3,4-dichlorophenyl)-3-C-methyl-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 425.266 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18Cl2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.92 Å3/Da / Density % sol: 57.83 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.1M Na-Cit,0.2M NaAc,11% PEG4000,pH6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97627 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 7, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97627 Å / Relative weight: 1
ReflectionResolution: 2.5→54.95 Å / Num. obs: 44312 / % possible obs: 99.6 % / Redundancy: 14 % / CC1/2: 0.984 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.017 / Rrim(I) all: 0.062 / Net I/σ(I): 25.4
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.6 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 4599 / CC1/2: 0.982 / Rpim(I) all: 0.162 / Rrim(I) all: 0.622 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.28data extraction
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→54.95 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.924 / SU B: 13.076 / SU ML: 0.264 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.433 / ESU R Free: 0.282 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2587 2205 5 %RANDOM
Rwork0.2046 ---
obs0.2072 42104 99.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 213.43 Å2 / Biso mean: 73.564 Å2 / Biso min: 42.53 Å2
Baniso -1Baniso -2Baniso -3
1-8.67 Å2-0 Å20 Å2
2---0.85 Å20 Å2
3----7.83 Å2
Refinement stepCycle: final / Resolution: 2.5→54.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7421 0 44 266 7731
Biso mean--58.9 62.5 -
Num. residues----938
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0137663
X-RAY DIFFRACTIONr_bond_other_d0.0010.0157058
X-RAY DIFFRACTIONr_angle_refined_deg1.2511.64410440
X-RAY DIFFRACTIONr_angle_other_deg1.0941.57516285
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3845936
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.39422.325400
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.245151230
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2551547
X-RAY DIFFRACTIONr_chiral_restr0.0450.2983
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.028681
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021777
X-RAY DIFFRACTIONr_mcbond_it3.1257.8323750
X-RAY DIFFRACTIONr_mcbond_other3.1227.8313749
X-RAY DIFFRACTIONr_mcangle_it5.22111.7394684
LS refinement shellResolution: 2.5→2.565 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 154 -
Rwork0.357 3057 -
all-3211 -
obs--99.01 %

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