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- PDB-7p2r: Crystal structure of mouse PRMT6 in complex with inhibitor EML980 -

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Basic information

Entry
Database: PDB / ID: 7p2r
TitleCrystal structure of mouse PRMT6 in complex with inhibitor EML980
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-4R7 / S-ADENOSYL-L-HOMOCYSTEINE / Protein arginine N-methyltransferase 6
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsBonnefond, L. / Cavarelli, J.
Funding support France, 4items
OrganizationGrant numberCountry
Agence Nationale de la Recherche (ANR)ANR-10-INSB-005 France
Agence Nationale de la Recherche (ANR)ANR-10-LABX-0030-INRT 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
DepositionJul 6, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 11, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 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 1.2Jan 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 6
B: Protein arginine N-methyltransferase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,5665
Polymers77,9092
Non-polymers1,6583
Water68538
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3300 Å2
ΔGint-34 kcal/mol
Surface area28090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.797, 118.687, 72.052
Angle α, β, γ (deg.)90.000, 102.790, 90.000
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Protein arginine N-methyltransferase 6 / Histone-arginine N-methyltransferase PRMT6


Mass: 38954.289 Da / Num. of mol.: 2 / Mutation: C53S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Prmt6, Hrmt1l6 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q6NZB1, type I protein arginine methyltransferase
#2: Chemical ChemComp-4R7 / methyl 6-[4-[[N-[2-[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]ethyl]carbamimidoyl]amino]butylcarbamoylamino]-4-oxidanyl-naphthalene-2-carboxylate


Mass: 636.659 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H36N10O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE / S-Adenosyl-L-homocysteine


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C14H20N6O5S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 38 / 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: 2.26 Å3/Da / Density % sol: 45.48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100 mM Tris-HCl pH 7.5, 200 mM CHOONa, 19 PEG 3,350

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Data collection

DiffractionMean temperature: 140 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: DECTRIS EIGER R 4M / Detector: PIXEL / Date: Nov 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.3→45.34 Å / Num. obs: 30031 / % possible obs: 98.6 % / Redundancy: 4 % / Biso Wilson estimate: 35.16 Å2 / CC1/2: 0.991 / CC star: 0.998 / Rmerge(I) obs: 0.1142 / Rpim(I) all: 0.06316 / Rrim(I) all: 0.1309 / Net I/σ(I): 9.24
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3 % / Rmerge(I) obs: 0.5127 / Mean I/σ(I) obs: 1.83 / Num. unique obs: 2717 / CC1/2: 0.782 / CC star: 0.937 / Rpim(I) all: 0.3282 / Rrim(I) all: 0.6123 / % possible all: 89.91

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
StructureStudiodata collection
DIALS3.3.3data reduction
DIALS3.3.3data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6SQ6

6sq6
PDB Unreleased entry


Resolution: 2.3→45.34 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 28.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2685 1446 4.82 %
Rwork0.1991 28566 -
obs0.2024 30012 98.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 256.69 Å2 / Biso mean: 40.7545 Å2 / Biso min: 16.38 Å2
Refinement stepCycle: final / Resolution: 2.3→45.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5240 0 118 38 5396
Biso mean--62.14 32.21 -
Num. residues----666
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.380.37071560.2652561271790
2.38-2.480.30871570.25432864302199
2.48-2.590.3571370.237628823019100
2.59-2.730.24811260.243928692995100
2.73-2.90.31881480.245228833031100
2.9-3.120.3531390.243328993038100
3.12-3.440.2961390.210328963035100
3.44-3.930.23911340.185829103044100
3.93-4.950.21181560.154728743030100
4.95-45.340.23621540.16482928308299

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