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- PDB-4x60: Crystal structure of PRMT5:MEP50 with EPZ015666 and sinefungin -

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Basic information

Entry
Database: PDB / ID: 4x60
TitleCrystal structure of PRMT5:MEP50 with EPZ015666 and sinefungin
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein-inhibitor complex / protein arginine methyltransferase / 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 / peptidyl-arginine methylation / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / Golgi ribbon formation / negative regulation of epithelial cell proliferation involved in prostate gland development / histone H4R3 methyltransferase activity / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / peptidyl-arginine methylation / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / Golgi ribbon formation / negative regulation of epithelial cell proliferation involved in prostate gland development / histone H4R3 methyltransferase activity / 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 / protein-arginine N-methyltransferase activity / methylosome / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / regulation of mitotic nuclear division / histone methyltransferase complex / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / positive regulation of oligodendrocyte differentiation / histone methyltransferase activity / E-box binding / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / ribonucleoprotein complex binding / spliceosomal snRNP assembly / regulation of ERK1 and ERK2 cascade / nuclear receptor coactivator activity / regulation of signal transduction by p53 class mediator / methyltransferase activity / liver regeneration / DNA-templated transcription termination / circadian regulation of gene expression / 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 / chromatin / regulation of transcription by RNA polymerase II / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Protein arginine N-methyltransferase PRMT5 / PRMT5 arginine-N-methyltransferase / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 ...: / Protein arginine N-methyltransferase PRMT5 / PRMT5 arginine-N-methyltransferase / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / Divalent-metal-dependent TIM barrel enzymes / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Vaccinia Virus protein VP39 / Distorted Sandwich / 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 / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / TIM Barrel / Alpha-Beta Barrel / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-3XV / SINEFUNGIN / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsBoriack-Sjodin, P.A.
CitationJournal: Nat.Chem.Biol. / Year: 2015
Title: A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.
Authors: Chan-Penebre, E. / Kuplast, K.G. / Majer, C.R. / Boriack-Sjodin, P.A. / Wigle, T.J. / Johnston, L.D. / Rioux, N. / Munchhof, M.J. / Jin, L. / Jacques, S.L. / West, K.A. / Lingaraj, T. / ...Authors: Chan-Penebre, E. / Kuplast, K.G. / Majer, C.R. / Boriack-Sjodin, P.A. / Wigle, T.J. / Johnston, L.D. / Rioux, N. / Munchhof, M.J. / Jin, L. / Jacques, S.L. / West, K.A. / Lingaraj, T. / Stickland, K. / Ribich, S.A. / Raimondi, A. / Scott, M.P. / Waters, N.J. / Pollock, R.M. / Smith, J.J. / Barbash, O. / Pappalardi, M. / Ho, T.F. / Nurse, K. / Oza, K.P. / Gallagher, K.T. / Kruger, R. / Moyer, M.P. / Copeland, R.A. / Chesworth, R. / Duncan, K.W.
History
DepositionDec 6, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2015Provider: repository / Type: Initial release
Revision 1.1May 13, 2015Group: Database references
Revision 1.2May 27, 2015Group: Structure summary
Revision 1.3Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list / struct_keywords
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text

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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)112,6677
Polymers111,6262
Non-polymers1,0415
Water2,486138
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4860 Å2
ΔGint-16 kcal/mol
Surface area37180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.670, 137.960, 179.010
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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
Source method: isolated from a genetically manipulated source
Details: coexpressed with MEP50 / Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O14744, Transferases; Transferring one-carbon groups; Methyltransferases, EC: 2.1.1.125
#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: coexpressed with PRMT5 / Source: (gene. exp.) Homo sapiens (human) / Gene: WDR77, MEP50, WD45, HKMT1069, Nbla10071 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BQA1

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Non-polymers , 4 types, 143 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-3XV / N-[(2S)-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl]-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide


Mass: 383.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25N5O3
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O

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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: 3.04 Å3/Da / Density % sol: 59.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.1
Details: 0.2 M Sodium acetate, 0.1 M Sodium citrate pH 6.1, 10% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 2, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.35→44.75 Å / Num. obs: 53483 / % possible obs: 99.6 % / Redundancy: 5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.052 / Rpim(I) all: 0.026 / Net I/σ(I): 21 / Num. measured all: 266192
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.35-2.4150.7522.51966639020.8050.37999.4
10.51-44.754.20.01966.726336330.9990.01195.4

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Processing

Software
NameVersionClassification
XDSdata reduction
REFMAC5.8.0073refinement
PDB_EXTRACT3.15data extraction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.35→44.75 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.935 / SU B: 11.15 / SU ML: 0.244 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.32 / ESU R Free: 0.245 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2537 2569 5 %RANDOM
Rwork0.202 48418 --
obs0.2046 48418 94.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 165.63 Å2 / Biso mean: 62.909 Å2 / Biso min: 32.28 Å2
Baniso -1Baniso -2Baniso -3
1-7.77 Å20 Å2-0 Å2
2---1.55 Å2-0 Å2
3----6.22 Å2
Refinement stepCycle: final / Resolution: 2.35→44.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7395 0 73 138 7606
Biso mean--52.28 51 -
Num. residues----935
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0197689
X-RAY DIFFRACTIONr_angle_refined_deg1.2421.95510472
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4365939
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.94423.949352
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.976151231
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7671547
X-RAY DIFFRACTIONr_chiral_restr0.0840.21154
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215874
X-RAY DIFFRACTIONr_mcbond_it3.2036.2453750
X-RAY DIFFRACTIONr_mcangle_it5.1699.3564685
X-RAY DIFFRACTIONr_scbond_it3.3186.3463939
LS refinement shellResolution: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 153 -
Rwork0.336 2922 -
all-3075 -
obs--78.4 %

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