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

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Basic information

Entry
Database: PDB / ID: 7zvl
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 / 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 / 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 / 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 / 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 H4R3 methyltransferase activity / histone H3K37 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 H2A Q104 methyltransferase activity / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / regulation of ERK1 and ERK2 cascade / spliceosomal snRNP assembly / ribonucleoprotein complex binding / : / 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 / 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. / 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 / 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
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: 2.39 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 16, 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
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)112,1437
Polymers111,6262
Non-polymers5175
Water2,432135
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5880 Å2
ΔGint-23 kcal/mol
Surface area36850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.576, 138.392, 178.493
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 , 5 types, 140 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: 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.: 135 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.78 Å3/Da / Density % sol: 55.79 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop
Details: 16% PEG3350, 100 mM Na citrate pH 5.4, 100mM Carboxylic acids

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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: 2.38→109.37 Å / Num. obs: 21837 / % possible obs: 85.56 % / Observed criterion σ(I): 1.85 / Redundancy: 11.5 % / CC1/2: 0.99 / Net I/σ(I): 12.8
Reflection shellResolution: 2.38→2.75 Å / Num. unique obs: 1092 / CC1/2: 0.83 / % possible all: 63

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.27data 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: 2.39→109.37 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.868 / SU B: 29.439 / SU ML: 0.326 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.554 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.286 1124 5.1 %RANDOM
Rwork0.2158 ---
obs0.2193 20713 43.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 229.22 Å2 / Biso mean: 65.392 Å2 / Biso min: 7.03 Å2
Baniso -1Baniso -2Baniso -3
1-0.28 Å20 Å20 Å2
2---2.95 Å2-0 Å2
3---2.67 Å2
Refinement stepCycle: final / Resolution: 2.39→109.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7399 0 46 135 7580
Biso mean--48.6 32.03 -
Num. residues----935
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0137662
X-RAY DIFFRACTIONr_bond_other_d0.0020.0176907
X-RAY DIFFRACTIONr_angle_refined_deg1.5661.64110443
X-RAY DIFFRACTIONr_angle_other_deg1.261.5716062
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4755937
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.4322.306399
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.715151231
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.781547
X-RAY DIFFRACTIONr_chiral_restr0.0640.2980
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028575
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021630
LS refinement shellResolution: 2.39→2.448 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.612 7 -
Rwork0.423 96 -
obs--2.83 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0368-0.1427-0.04510.71080.10261.11640.03560.0229-0.0041-0.09540.0062-0.0239-0.16370.4653-0.04170.1245-0.04630.02880.4145-0.04110.067420.642-61.3765-19.3429
21.02650.4186-0.56351.0367-0.13342.2948-0.12620.126-0.06-0.21940.1646-0.08681.07230.7283-0.03840.82040.5639-0.02630.616-0.0980.029528.3126-110.8105-37.6205
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A13 - 1001
2X-RAY DIFFRACTION2B19 - 328

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