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- PDB-7u30: PRMT5:MEP50 Complexed with Cyclonucleoside Compound 1 -

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Basic information

Entry
Database: PDB / ID: 7u30
TitlePRMT5:MEP50 Complexed with Cyclonucleoside Compound 1
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / PRMT5 / Inhibitor / Cyclonucleoside / Methyl Transferase
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. / Divalent-metal-dependent TIM barrel enzymes / 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 / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-LB3 / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsPalte, R.L.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity.
Authors: Kawamura, S. / Palte, R.L. / Kim, H.Y. / Sauri, J. / Sondey, C. / Mansueto, M.S. / Altman, M.D. / Machacek, M.R.
History
DepositionFeb 25, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 1, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)109,46111
Polymers108,5612
Non-polymers9019
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5300 Å2
ΔGint2 kcal/mol
Surface area38060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.418, 138.742, 178.704
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-882-

HOH

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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: 73763.625 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: 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: 34796.934 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: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BQA1
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-LB3 / (9R,10R,11S,12R,13R,14R)-4-amino-9-(3,4-difluorophenyl)-6,7,8,9,10,11,12,13-octahydro-10,13-epoxy[1,3]diazecino[1,2-e]purine-11,12-diol


Mass: 404.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18F2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 94 / Source method: isolated from a natural source / Formula: H2O
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: 2.98 Å3/Da / Density % sol: 58.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.1 M sodium citrate pH 6.0, 0.2 M sodium acetate, 10-12% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.116 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.116 Å / Relative weight: 1
ReflectionResolution: 2.6→90.16 Å / Num. obs: 40073 / % possible obs: 99.5 % / Redundancy: 13.5 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 26.2
Reflection shellResolution: 2.6→2.71 Å / Rmerge(I) obs: 1.296 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 4451

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
HKL-3000data reduction
HKL-3000data scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OOP

5oop


Resolution: 2.6→89.35 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.923 / SU R Cruickshank DPI: 0.481 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.462 / SU Rfree Blow DPI: 0.23 / SU Rfree Cruickshank DPI: 0.235
RfactorNum. reflection% reflectionSelection details
Rfree0.208 1994 4.98 %RANDOM
Rwork0.21 ---
obs0.21 40072 99.5 %-
Displacement parametersBiso max: 196.45 Å2 / Biso mean: 89.67 Å2 / Biso min: 41.3 Å2
Baniso -1Baniso -2Baniso -3
1-0.9836 Å20 Å20 Å2
2--1.0925 Å20 Å2
3----2.0761 Å2
Refine analyzeLuzzati coordinate error obs: 0.41 Å
Refinement stepCycle: final / Resolution: 2.6→89.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7408 0 61 94 7563
Biso mean--86.07 76.37 -
Num. residues----936
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2590SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1318HARMONIC3
X-RAY DIFFRACTIONt_it7682HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion978SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8616SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7682HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10460HARMONIC30.87
X-RAY DIFFRACTIONt_omega_torsion4.93
X-RAY DIFFRACTIONt_other_torsion19.7
LS refinement shellResolution: 2.6→2.62 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2805 35 4.36 %
Rwork0.2939 767 -
all0.2933 802 -
obs--98.99 %

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