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- PDB-9mgq: Crystal structure of PRMT5:MEP50 in complex with sinefungin and c... -

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Basic information

Entry
Database: PDB / ID: 9mgq
TitleCrystal structure of PRMT5:MEP50 in complex with sinefungin and compound 47
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
: / DI(HYDROXYETHYL)ETHER / SINEFUNGIN / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 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

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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)114,64034
Polymers111,6262
Non-polymers3,01432
Water6,648369
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)458,560136
Polymers446,5048
Non-polymers12,056128
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
Unit cell
Length a, b, c (Å)101.660, 137.700, 178.000
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 , 6 types, 401 molecules

#3: Chemical ChemComp-SFG / SINEFUNGIN / ADENOSYL-ORNITHINE


Mass: 381.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H23N7O5
#4: Chemical ChemComp-A1BLG / 2-(cyclobutylamino)-N-{(2R)-2-hydroxy-2-[(3S)-1,2,3,4-tetrahydroisoquinolin-3-yl]ethyl}pyridine-4-carboxamide


Mass: 366.457 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H26N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 19 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 369 / 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: 2.79 Å3/Da / Density % sol: 55.92 %
Crystal growTemperature: 283 K / Method: vapor diffusion, hanging drop
Details: 25% PEG 3350, 0.1 M Bis-Tris (pH 5.5), 0.2 M ammonium sulfate
PH range: 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.85→108.91 Å / Num. obs: 74746 / % possible obs: 94.4 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.041 / Net I/σ(I): 14.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) all% possible all
5.02-108.910.03739.655630.9990.01699.3
1.85-1.886.71.5951.51420.0570.668

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→37 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.914 / SU R Cruickshank DPI: 0.179 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.178 / SU Rfree Blow DPI: 0.163 / SU Rfree Cruickshank DPI: 0.164
RfactorNum. reflection% reflectionSelection details
Rfree0.242 3690 4.94 %RANDOM
Rwork0.199 ---
obs0.202 74731 70.3 %-
Displacement parametersBiso mean: 37.61 Å2
Baniso -1Baniso -2Baniso -3
1--0.8989 Å20 Å20 Å2
2--0.1054 Å20 Å2
3---0.7935 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 1.85→37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7364 0 191 369 7924
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0087941HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0110921HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2668SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes187HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1146HARMONIC5
X-RAY DIFFRACTIONt_it7941HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion17.44
X-RAY DIFFRACTIONt_chiral_improper_torsion981SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact9158SEMIHARMONIC4
LS refinement shellResolution: 1.85→1.9 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.224 -4.81 %
Rwork0.215 277 -
all0.215 291 -
obs--3.73 %

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