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- PDB-6k1s: Discovery of Potent and Selective Covalent Protein Arginine Methy... -

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Basic information

Entry
Database: PDB / ID: 6k1s
TitleDiscovery of Potent and Selective Covalent Protein Arginine Methyltransferase (PRMT5) Inhibitors
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / PRMT5 / complex / covalent / inhibitor
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 H4R3 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 H4R3 methyltransferase activity / : / epithelial cell proliferation involved in prostate gland development / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase activity / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of gene expression via chromosomal CpG island methylation / E-box binding / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / spliceosomal snRNP assembly / regulation of ERK1 and ERK2 cascade / ribonucleoprotein complex binding / ubiquitin-like ligase-substrate adaptor activity / liver regeneration / regulation of signal transduction by p53 class mediator / methyltransferase activity / Regulation of TP53 Activity through Methylation / circadian regulation of gene expression / DNA-templated transcription termination / RMTs methylate histone arginines / protein polyubiquitination / p53 binding / transcription corepressor activity / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / chromatin remodeling / protein heterodimerization activity / positive regulation of cell population proliferation / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / 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 / Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 ...: / 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 / 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 / Vaccinia Virus protein VP39 / 7 Propeller / Methylamine Dehydrogenase; Chain H / Distorted Sandwich / WD domain, G-beta repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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-CUX / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.6 Å
AuthorsTong, S. / Lin, H.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors.
Authors: Lin, H. / Wang, M. / Zhang, Y.W. / Tong, S. / Leal, R.A. / Shetty, R. / Vaddi, K. / Luengo, J.I.
History
DepositionMay 12, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 31, 2019Group: Data collection / 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_author.identifier_ORCID
Revision 1.2Nov 22, 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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)112,55711
Polymers111,6262
Non-polymers9319
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5990 Å2
ΔGint12 kcal/mol
Surface area37680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.639, 138.724, 178.022
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Spodoptera frugiperda (fall armyworm)
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: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BQA1

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Non-polymers , 4 types, 110 molecules

#3: Chemical ChemComp-CUX / 2-[[7-[(2~{R},3~{R},4~{S},5~{R})-5-[(~{R})-(4-chlorophenyl)-oxidanyl-methyl]-3,4-bis(oxidanyl)oxolan-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]ethanal


Mass: 418.831 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19ClN4O5
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.84 Å3/Da / Density % sol: 56.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.1M Na-Citrate, pH6.0 0.2M NaAc 12% PEG4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 37407 / % possible obs: 93.4 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.093 / Net I/σ(I): 5.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.6-2.695.30.63127140.8540.2840.6940.93269.1
2.69-2.85.50.58831550.8860.2640.6460.95779.4
2.8-2.935.90.46434800.9420.2020.5070.96188.1
2.93-3.086.40.36838280.9750.1550.40.95996.9
3.08-3.286.80.26439990.9830.1090.2860.95999.8
3.28-3.536.80.16939430.9920.070.1840.977100
3.53-3.886.40.10240220.9970.0440.1110.972100
3.88-4.4570.07140290.9980.0290.0770.949100
4.45-5.66.40.05340340.9980.0230.0580.893100
5.6-506.60.04242030.9980.0180.0450.78199.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQB

4gqb


Resolution: 2.6→50 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.917 / SU B: 18.325 / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.681 / ESU R Free: 0.341 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.275 1876 5 %RANDOM
Rwork0.212 ---
obs0.216 35506 92.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 74.99 Å2
Baniso -1Baniso -2Baniso -3
1-11.55 Å20 Å20 Å2
2---3.79 Å20 Å2
3----7.77 Å2
Refinement stepCycle: LAST / Resolution: 2.6→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7379 0 60 101 7540
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0197642
X-RAY DIFFRACTIONr_bond_other_d0.0020.026900
X-RAY DIFFRACTIONr_angle_refined_deg1.3491.95210394
X-RAY DIFFRACTIONr_angle_other_deg0.9473.00116036
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1555931
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94623.949352
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.404151226
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.651547
X-RAY DIFFRACTIONr_chiral_restr0.0710.21143
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0218460
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021576
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.65 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.49 104 -
Rwork0.389 1653 -
obs--60.32 %

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