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- PDB-9mgr: Crystal structure of PRMT5:MEP50 in complex with MTA and compound 51 -

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Basic information

Entry
Database: PDB / ID: 9mgr
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and compound 51
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 / peptidyl-arginine methylation / protein-arginine omega-N symmetric methyltransferase activity / 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 / peptidyl-arginine methylation / protein-arginine omega-N symmetric methyltransferase activity / 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 H4R3 methyltransferase activity / histone H3K37 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 H2A Q104 methyltransferase activity / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / regulation of ERK1 and ERK2 cascade / spliceosomal snRNP assembly / ribonucleoprotein complex binding / : / 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 / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / 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
: / 5'-DEOXY-5'-METHYLTHIOADENOSINE / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 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)113,47319
Polymers111,6262
Non-polymers1,84717
Water2,378132
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)453,89276
Polymers446,5048
Non-polymers7,38868
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 area46710 Å2
ΔGint83 kcal/mol
Surface area130840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.946, 137.889, 178.607
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 , 4 types, 149 molecules

#3: Chemical ChemComp-A1BLF / 6-[(1-acetylazetidin-3-yl)amino]-N-[(2R)-2-hydroxy-2-{(3S)-7-[(4-methyl-1,3-oxazol-5-yl)methoxy]-1,2,3,4-tetrahydroisoquinolin-3-yl}ethyl]-2-(4-methylpiperidin-1-yl)pyrimidine-4-carboxamide


Mass: 618.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42N8O5 / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.84 Å3/Da / Density % sol: 56.68 %
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: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Jun 21, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.07→109.15 Å / Num. obs: 36863 / % possible obs: 93.5 % / Redundancy: 13.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.16 / Rpim(I) all: 0.045 / Net I/σ(I): 12.9
Reflection shell

Num. unique obs: 1843 / Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsCC1/2Rpim(I) all% possible all
7.41-109.1513.30.04242.20.9990.012100
2.07-2.36511.11.3431.90.7580.4281.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
DIALSdata reduction
DIALSdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→109.15 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.875 / SU B: 6.928 / SU ML: 0.18 / Cross valid method: THROUGHOUT / ESU R: 0.815 / ESU R Free: 0.345 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27273 1825 5 %RANDOM
Rwork0.22165 ---
obs0.2241 35038 47.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 42.548 Å2
Baniso -1Baniso -2Baniso -3
1-0.46 Å2-0 Å20 Å2
2---0.38 Å2-0 Å2
3----0.09 Å2
Refinement stepCycle: 1 / Resolution: 2.07→109.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7313 0 125 132 7570
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0127789
X-RAY DIFFRACTIONr_bond_other_d0.0010.0167209
X-RAY DIFFRACTIONr_angle_refined_deg1.0051.8310599
X-RAY DIFFRACTIONr_angle_other_deg0.3561.75816637
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.255953
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.608551
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.888101258
X-RAY DIFFRACTIONr_chiral_restr0.0450.21154
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029266
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021815
X-RAY DIFFRACTIONr_mcbond_it1.374.383773
X-RAY DIFFRACTIONr_mcbond_other1.374.383773
X-RAY DIFFRACTIONr_mcangle_it2.4677.8584739
X-RAY DIFFRACTIONr_mcangle_other2.4677.8594740
X-RAY DIFFRACTIONr_scbond_it0.9954.4214016
X-RAY DIFFRACTIONr_scbond_other0.9954.4214017
X-RAY DIFFRACTIONr_scangle_other1.8458.1035859
X-RAY DIFFRACTIONr_long_range_B_refined4.45540.948501
X-RAY DIFFRACTIONr_long_range_B_other4.45440.948500
LS refinement shellResolution: 2.071→2.125 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.432 7 -
Rwork0.318 140 -
obs--2.59 %

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