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- PDB-7zuy: HUMAN PRMT5:MEP50 Crystal Structure With MTA and Fragment Bound -

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Basic information

Entry
Database: PDB / ID: 7zuy
TitleHUMAN PRMT5:MEP50 Crystal Structure With MTA and Fragment Bound
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / MTAP / methyl transferase / fragment-based lead discovery / FBDD
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 / 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 / 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 / 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 / methylosome / protein-arginine N-methyltransferase activity / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / regulation of mitotic nuclear division / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / histone methyltransferase activity / E-box binding / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / ribonucleoprotein complex binding / 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 / cytoplasm / cytosol
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 / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / WD40 repeat, conserved site ...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 / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / 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
Similarity search - Domain/homology
5'-DEOXY-5'-METHYLTHIOADENOSINE / Unknown ligand / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAhmad, M.U. / Koelmel, W. / Arkhipova, V. / Lawson, J.D. / Smith, C.R. / Gunn, R.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Rsc Med Chem / Year: 2022
Title: Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.
Authors: Smith, C.R. / Kulyk, S. / Ahmad, M.U.D. / Arkhipova, V. / Christensen, J.G. / Gunn, R.J. / Ivetac, A. / Ketcham, J.M. / Kuehler, J. / Lawson, J.D. / Thomas, N.C. / Wang, X. / Marx, M.A.
History
DepositionMay 13, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 19, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2023Group: 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_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)112,1086
Polymers111,6262
Non-polymers4824
Water4,612256
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5970 Å2
ΔGint-10 kcal/mol
Surface area36860 Å2
Unit cell
Length a, b, c (Å)105.262, 139.037, 178.421
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
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, 260 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-UNL / UNKNOWN LIGAND


Num. of mol.: 1 / Source method: obtained synthetically / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / 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: 2.92 Å3/Da / Density % sol: 57.94 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop
Details: 13 % PEG3350, 100 mM Na citrate, pH 5.4, 4% Tacsimate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9197 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jul 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9197 Å / Relative weight: 1
ReflectionResolution: 1.97→109.67 Å / Num. obs: 48889 / % possible obs: 93.7 % / Observed criterion σ(I): 1.74 / Redundancy: 11.8 % / CC1/2: 0.99 / Net I/σ(I): 12.8
Reflection shellResolution: 1.97→2.23 Å / Num. unique obs: 2444 / CC1/2: 0.74 / % possible all: 77.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.22data extraction
XDSFeb 5, 2021 (BUILT 20210323)data reduction
Aimless0.7.7data scaling
REFMAC5.8.0267phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EML

5eml


Resolution: 2→109.67 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.899 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.085 / ESU R Free: 0.059 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2698 2523 5.2 %RANDOM
Rwork0.222 ---
obs0.2245 45692 54.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.75 Å2 / Biso mean: 31.269 Å2 / Biso min: 17.3 Å2
Baniso -1Baniso -2Baniso -3
1-1.8 Å20 Å20 Å2
2---0.71 Å2-0 Å2
3----1.09 Å2
Refinement stepCycle: final / Resolution: 2→109.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7399 0 52 256 7707
Biso mean--29.46 37.28 -
Num. residues----935
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0137679
X-RAY DIFFRACTIONr_bond_other_d0.0350.0176915
X-RAY DIFFRACTIONr_angle_refined_deg1.4871.64510468
X-RAY DIFFRACTIONr_angle_other_deg2.3261.57316080
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3735939
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.54222.325400
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.661151233
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6531547
X-RAY DIFFRACTIONr_chiral_restr0.0630.2981
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028594
X-RAY DIFFRACTIONr_gen_planes_other0.0090.021631
X-RAY DIFFRACTIONr_mcbond_it1.5763.3113752
X-RAY DIFFRACTIONr_mcbond_other1.5763.3113751
X-RAY DIFFRACTIONr_mcangle_it2.7544.9624693
LS refinement shellResolution: 2.002→2.054 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.347 10 -
Rwork0.305 143 -
all-153 -
obs--2.38 %

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