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- PDB-6uxx: PRMT5:MEP50 Complexed with Allosteric Inhibitor Compound 1a -

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Basic information

Entry
Database: PDB / ID: 6uxx
TitlePRMT5:MEP50 Complexed with Allosteric Inhibitor Compound 1a
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/Transcription / Methyltransferase / PRMT5 / Protein Arginine Methyltransferase 5 / allosteric inhibition / peptide competitive / SAM competitive / TRANSFERASE / TRANSFERASE-Transcription 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. / Divalent-metal-dependent TIM barrel enzymes / 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 / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-QL1 / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 Å
AuthorsPalte, R.L. / Schneider, S.E.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5).
Authors: Palte, R.L. / Schneider, S.E. / Altman, M.D. / Hayes, R.P. / Kawamura, S. / Lacey, B.M. / Mansueto, M.S. / Reutershan, M. / Siliphaivanh, P. / Sondey, C. / Xu, H. / Xu, Z. / Ye, Y. / Machacek, M.R.
History
DepositionNov 8, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)111,9793
Polymers111,6262
Non-polymers3531
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4260 Å2
ΔGint-13 kcal/mol
Surface area38260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.071, 138.775, 178.557
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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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: 37862.406 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-QL1 / (5R)-2-amino-5-(4-methoxyphenyl)-3-methyl-5-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]decan-1-yl]-3,5-dihydro-4H-imidazol-4-one


Mass: 353.458 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.86 Å3/Da / Density % sol: 56.99 %
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: SSRF / Beamline: BL19U1 / Wavelength: 0.97776 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 18, 2017
RadiationMonochromator: LN2-cooled DCM with Si(111) crystals / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97776 Å / Relative weight: 1
ReflectionResolution: 2.69→50 Å / Num. obs: 35543 / % possible obs: 99 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 23.9
Reflection shellResolution: 2.69→2.79 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.65 / Num. unique obs: 3363

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
HKL-3000data reduction
HKL-3000data scaling
HKL-3000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4gqb

4gqb


Resolution: 2.69→34.58 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.903 / SU R Cruickshank DPI: 0.766 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.719 / SU Rfree Blow DPI: 0.331 / SU Rfree Cruickshank DPI: 0.339
RfactorNum. reflection% reflectionSelection details
Rfree0.277 1765 4.97 %RANDOM
Rwork0.259 ---
obs0.26 35525 98.9 %-
Displacement parametersBiso max: 185.03 Å2 / Biso mean: 91.35 Å2 / Biso min: 45.44 Å2
Baniso -1Baniso -2Baniso -3
1--0.497 Å20 Å20 Å2
2--1.9481 Å20 Å2
3----1.4511 Å2
Refine analyzeLuzzati coordinate error obs: 0.7 Å
Refinement stepCycle: final / Resolution: 2.69→34.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7272 0 26 57 7355
Biso mean--64.45 71.09 -
Num. residues----920
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2529SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes180HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1096HARMONIC5
X-RAY DIFFRACTIONt_it7498HARMONIC30
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion958SEMIHARMONIC5
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_contact8095SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7498HARMONIC10.014
X-RAY DIFFRACTIONt_angle_deg10223HARMONIC30.67
X-RAY DIFFRACTIONt_omega_torsion2.12
X-RAY DIFFRACTIONt_other_torsion19.38
LS refinement shellResolution: 2.69→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.3505 121 4.39 %
Rwork0.3381 2636 -
all0.3386 2757 -
obs--94.35 %

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