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- PDB-7nud: Crystal structure of mouse PRMT6 in complex with inhibitor EML734 -

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Basic information

Entry
Database: PDB / ID: 7nud
TitleCrystal structure of mouse PRMT6 in complex with inhibitor EML734
ComponentsProtein arginine N-methyltransferase 6
KeywordsTRANSFERASE / SAM binding domain / arginine methylation
Function / homology
Function and homology information


histone H2AR3 methyltransferase activity / peptidyl-arginine methylation, to asymmetrical-dimethyl arginine / protein-arginine omega-N monomethyltransferase activity / histone H4R3 methyltransferase activity / histone H3R2 methyltransferase activity / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / RMTs methylate histone arginines / type I protein arginine methyltransferase / protein-arginine omega-N asymmetric methyltransferase activity / histone arginine N-methyltransferase activity ...histone H2AR3 methyltransferase activity / peptidyl-arginine methylation, to asymmetrical-dimethyl arginine / protein-arginine omega-N monomethyltransferase activity / histone H4R3 methyltransferase activity / histone H3R2 methyltransferase activity / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / RMTs methylate histone arginines / type I protein arginine methyltransferase / protein-arginine omega-N asymmetric methyltransferase activity / histone arginine N-methyltransferase activity / protein-arginine N-methyltransferase activity / regulation of mitochondrion organization / histone H3 methyltransferase activity / histone methyltransferase activity / negative regulation of ubiquitin-dependent protein catabolic process / regulation of signal transduction by p53 class mediator / protein modification process / cellular senescence / histone binding / DNA repair / negative regulation of DNA-templated transcription / chromatin binding / nucleolus / negative regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Methyltransferase domain 25 / Methyltransferase domain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Chem-LRZ / Protein arginine N-methyltransferase 6
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.65 Å
AuthorsBonnefond, L. / Cavarelli, J.
Funding support France, 4items
OrganizationGrant numberCountry
Agence Nationale de la Recherche (ANR)ANR-10-LABX-0030-INRT France
Agence Nationale de la Recherche (ANR)ANR-10-INSB-005 France
Agence Nationale de la Recherche (ANR)ANR-19-CE11-0010-01 JC France
Fondation ARCPJA 20161204817 France
CitationJournal: J.Med.Chem. / Year: 2022
Title: Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction- ...Title: Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction-Reconstruction and Fragment-Growing Approach.
Authors: Iannelli, G. / Milite, C. / Marechal, N. / Cura, V. / Bonnefond, L. / Troffer-Charlier, N. / Feoli, A. / Rescigno, D. / Wang, Y. / Cipriano, A. / Viviano, M. / Bedford, M.T. / Cavarelli, J. ...Authors: Iannelli, G. / Milite, C. / Marechal, N. / Cura, V. / Bonnefond, L. / Troffer-Charlier, N. / Feoli, A. / Rescigno, D. / Wang, Y. / Cipriano, A. / Viviano, M. / Bedford, M.T. / Cavarelli, J. / Castellano, S. / Sbardella, G.
History
DepositionMar 11, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Sep 21, 2022Group: 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
Revision 1.3Jan 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 6
B: Protein arginine N-methyltransferase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,8604
Polymers85,6432
Non-polymers1,2172
Water2,504139
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3370 Å2
ΔGint-30 kcal/mol
Surface area27580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.766, 118.147, 71.998
Angle α, β, γ (deg.)90.000, 104.320, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Protein arginine N-methyltransferase 6


Mass: 42821.301 Da / Num. of mol.: 2 / Fragment: mouse PRMT6 / Mutation: F315L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Prmt6, Hrmt1l6 / Plasmid: pET15b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q6NZB1, type I protein arginine methyltransferase
#2: Chemical ChemComp-LRZ / methyl 6-[3-[[~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]carbamimidoyl]amino]propylcarbamoylamino]-4-oxidanyl-naphthalene-2-carboxylate


Mass: 608.606 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C27H32N10O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O
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: 2.35 Å3/Da / Density % sol: 47.65 % / Mosaicity: 0.31 °
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5
Details: PEG 3,350 20%, NaNO3 200 mM, Tris-HCl pH 7.5 100 mM

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Mar 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.65→45.08 Å / Num. obs: 81095 / % possible obs: 99.6 % / Redundancy: 18.5 % / Biso Wilson estimate: 21.32 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.12 / Rpim(I) all: 0.028 / Rrim(I) all: 0.123 / Net I/σ(I): 14.9
Reflection shellResolution: 1.65→1.68 Å / Redundancy: 7.3 % / Rmerge(I) obs: 2.058 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4071 / CC1/2: 0.479 / Rpim(I) all: 0.802 / Rrim(I) all: 2.215 / % possible all: 99.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimless0.7.3data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4C03

4c03


Resolution: 1.65→39.5 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2139 3969 4.9 %
Rwork0.1968 77110 -
obs0.1977 81079 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 132.1 Å2 / Biso mean: 33.7923 Å2 / Biso min: 14.3 Å2
Refinement stepCycle: final / Resolution: 1.65→39.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5148 0 152 139 5439
Biso mean--47.11 29.82 -
Num. residues----655
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.65-1.670.33791390.31482811
1.67-1.690.31071440.28352708
1.69-1.710.30951510.26552725
1.71-1.740.2891510.2532744
1.74-1.760.28161560.24772735
1.76-1.790.29941480.26682711
1.79-1.820.33621500.27712776
1.82-1.850.28991480.26612719
1.85-1.880.32311260.24742746
1.88-1.910.28021770.24332717
1.91-1.950.26141110.21422781
1.95-1.990.24041390.20172777
1.99-2.030.22991360.20372701
2.03-2.080.22011450.20512783
2.08-2.130.21641330.21572740
2.13-2.190.24091240.21982781
2.19-2.250.24671130.20072757
2.25-2.330.24691480.19752795
2.33-2.410.21881460.19582719
2.41-2.510.26381330.19732750

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