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- PDB-9mgn: Crystal structure of PRMT5:MEP50 in complex with MTA and compound 41 -

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Basic information

Entry
Database: PDB / ID: 9mgn
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and compound 41
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / methyltransferase / inhibitor / MTAP-null / TRANSFERASE / TRANSFERASE-INHIBITOR 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 H4R3 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 H4R3 methyltransferase activity / : / epithelial cell proliferation involved in prostate gland development / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / histone methyltransferase activity / regulation of mitotic nuclear division / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / E-box binding / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / ubiquitin-like ligase-substrate adaptor activity / 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 / p53 binding / transcription corepressor activity / 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 / cytoplasm / cytosol
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 / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
: / 5'-DEOXY-5'-METHYLTHIOADENOSINE / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.82 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design.
Authors: Cottrell, K.M. / Whittington, D.A. / Briggs, K.J. / Jahic, H. / Ali, J.A. / Amor, A.J. / Gotur, D. / Tonini, M.R. / Zhang, W. / Huang, A. / Maxwell, J.P.
History
DepositionDec 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,6167
Polymers111,6262
Non-polymers9905
Water1086
1
A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules


Theoretical massNumber of molelcules
Total (without water)450,46528
Polymers446,5048
Non-polymers3,96120
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area37170 Å2
ΔGint-77 kcal/mol
Surface area135290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.650, 137.840, 179.090
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 2 types, 2 molecules AB

#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: 73763.625 Da / Num. of mol.: 1 / Fragment: FULL LENGTH
Source method: isolated from a genetically manipulated source
Details: N-terminal Flag tag / Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Trichoplusia ni (cabbage looper)
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: 37862.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal His-8 tag / Source: (gene. exp.) Homo sapiens (human) / Gene: WDR77, MEP50, WD45, HKMT1069, Nbla10071 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BQA1

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Non-polymers , 5 types, 11 molecules

#3: Chemical ChemComp-A1BLK / 2-(cyclobutylamino)-N-[(2S)-2-hydroxy-3-{6-[(1H-pyrazol-4-yl)methoxy]-3,4-dihydroisoquinolin-2(1H)-yl}propyl]pyridine-4-carboxamide


Mass: 476.571 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H32N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.81 Å3/Da / Density % sol: 56.23 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 10% PEG 4000, 0.1 M sodium citrate (pH 6.0), 0.2 M magnesium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07812 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07812 Å / Relative weight: 1
ReflectionResolution: 2.82→44.8 Å / Num. obs: 30319 / % possible obs: 98.9 % / Redundancy: 13.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.034 / Rrim(I) all: 0.126 / Χ2: 1 / Net I/σ(I): 14.2
Reflection shellResolution: 2.82→2.89 Å / % possible obs: 98.4 % / Redundancy: 14.1 % / Rmerge(I) obs: 1.154 / Num. measured all: 30718 / Num. unique obs: 2184 / CC1/2: 0.924 / Rpim(I) all: 0.317 / Rrim(I) all: 1.197 / Χ2: 0.94 / Net I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
Aimlessdata scaling
XDSdata reduction
REFMAC5.8.0238phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.82→44.8 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.917 / SU B: 31.825 / SU ML: 0.522 / Cross valid method: THROUGHOUT / ESU R Free: 0.412 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28094 1500 4.9 %RANDOM
Rwork0.22868 ---
obs0.23134 28805 98.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 86.3 Å2
Baniso -1Baniso -2Baniso -3
1-14.11 Å2-0 Å2-0 Å2
2---1.25 Å2-0 Å2
3----12.86 Å2
Refinement stepCycle: 1 / Resolution: 2.82→44.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7391 0 69 6 7466
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0137663
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176908
X-RAY DIFFRACTIONr_angle_refined_deg1.2921.64910437
X-RAY DIFFRACTIONr_angle_other_deg1.0811.57716062
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6115932
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.07522.306399
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.563151225
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.1981547
X-RAY DIFFRACTIONr_chiral_restr0.0440.2979
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.028551
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021631
X-RAY DIFFRACTIONr_mcbond_it1.9029.363734
X-RAY DIFFRACTIONr_mcbond_other1.9029.363733
X-RAY DIFFRACTIONr_mcangle_it3.37514.0374664
X-RAY DIFFRACTIONr_mcangle_other3.37414.0374665
X-RAY DIFFRACTIONr_scbond_it1.3859.4133927
X-RAY DIFFRACTIONr_scbond_other1.3859.4123928
X-RAY DIFFRACTIONr_scangle_other2.54914.0745772
LS refinement shellResolution: 2.82→2.893 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.433 100 -
Rwork0.457 2081 -
obs--98.2 %

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