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- PDB-8vet: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide ... -

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Basic information

Entry
Database: PDB / ID: 8vet
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 1
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / MTAP-null / SAM / MTA / MTA-cooperative / 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 / 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 / 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. / 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
Similarity search - Domain/homology
: / 5'-DEOXY-5'-METHYLTHIOADENOSINE / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.63 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP -Deleted Cancers.
Authors: Cottrell, K.M. / Briggs, K.J. / Whittington, D.A. / Jahic, H. / Ali, J.A. / Davis, C.B. / Gong, S. / Gotur, D. / Gu, L. / McCarren, P. / Tonini, M.R. / Tsai, A. / Wilker, E.W. / Yuan, H. / ...Authors: Cottrell, K.M. / Briggs, K.J. / Whittington, D.A. / Jahic, H. / Ali, J.A. / Davis, C.B. / Gong, S. / Gotur, D. / Gu, L. / McCarren, P. / Tonini, M.R. / Tsai, A. / Wilker, E.W. / Yuan, H. / Zhang, M. / Zhang, W. / Huang, A. / Maxwell, J.P.
History
DepositionDec 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)112,3476
Polymers111,6262
Non-polymers7214
Water52229
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5970 Å2
ΔGint-19 kcal/mol
Surface area37320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.190, 137.030, 178.880
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
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

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Non-polymers , 5 types, 33 molecules

#3: Chemical ChemComp-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1AAS / N-(5-methylpyridin-3-yl)-2-[(2R)-2-(1-methyl-1H-pyrrol-2-yl)piperidin-1-yl]-2-oxoacetamide


Mass: 326.393 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H22N4O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.83 Å3/Da / Density % sol: 56.57 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6.5
Details: 10% PEG 4000, 0.2M magnesium chloride, 0.1M MES (pH 6.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07812 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Mar 2, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07812 Å / Relative weight: 1
ReflectionResolution: 2.63→44.7 Å / Num. obs: 37944 / % possible obs: 99.8 % / Redundancy: 13.5 % / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.025 / Rrim(I) all: 0.091 / Χ2: 0.98 / Net I/σ(I): 19.6
Reflection shellResolution: 2.63→2.7 Å / % possible obs: 99.8 % / Redundancy: 13 % / Rmerge(I) obs: 1.451 / Num. measured all: 35949 / Num. unique obs: 2774 / CC1/2: 0.894 / Rpim(I) all: 0.416 / Rrim(I) all: 1.51 / Χ2: 0.91 / Net I/σ(I) obs: 1.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
Aimlessdata scaling
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.63→44.7 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.916 / SU B: 21.313 / SU ML: 0.389 / Cross valid method: THROUGHOUT / ESU R: 0.665 / ESU R Free: 0.338 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27691 1931 5.1 %RANDOM
Rwork0.22426 ---
obs0.22691 36007 99.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 82.204 Å2
Baniso -1Baniso -2Baniso -3
1-12.69 Å20 Å2-0 Å2
2---2.78 Å20 Å2
3----9.92 Å2
Refinement stepCycle: 1 / Resolution: 2.63→44.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7399 0 49 29 7477
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0137649
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176898
X-RAY DIFFRACTIONr_angle_refined_deg1.3121.64610423
X-RAY DIFFRACTIONr_angle_other_deg1.0841.57516037
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9355933
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.05322.306399
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.422151227
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0991547
X-RAY DIFFRACTIONr_chiral_restr0.0480.2979
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.028554
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021627
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_it1.7278.9163738
X-RAY DIFFRACTIONr_mcbond_other1.7278.9153737
X-RAY DIFFRACTIONr_mcangle_it3.12713.3714669
X-RAY DIFFRACTIONr_mcangle_other3.12713.3714670
X-RAY DIFFRACTIONr_scbond_it1.1798.9543909
X-RAY DIFFRACTIONr_scbond_other1.1798.9543910
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.25113.3855755
X-RAY DIFFRACTIONr_long_range_B_refined5.10299.9018022
X-RAY DIFFRACTIONr_long_range_B_other5.10299.8998022
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.63→2.698 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.427 129 -
Rwork0.458 2642 -
obs--99.75 %

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