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- PDB-7nue: Crystal structure of mouse PRMT6 in complex with inhibitor EML736 -

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Basic information

Entry
Database: PDB / ID: 7nue
TitleCrystal structure of mouse PRMT6 in complex with inhibitor EML736
ComponentsProtein arginine N-methyltransferase 6
KeywordsTRANSFERASE / SAM binding domain / arginine methylation
Function / homology
Function and homology information


histone H2AR3 methyltransferase activity / protein-arginine omega-N monomethyltransferase 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 H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / histone H3R8 methyltransferase activity ...histone H2AR3 methyltransferase activity / protein-arginine omega-N monomethyltransferase 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 H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / histone H3R8 methyltransferase activity / histone H3R26 methyltransferase activity / histone H3K37 methyltransferase activity / histone H4R3 methyltransferase activity / histone H4K12 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / regulation of mitochondrion organization / histone H2AQ104 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 / methylation / 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
: / Arginine methyltransferase oligomerization subdomain / 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-LSK / Protein arginine N-methyltransferase 6
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 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
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)87,0304
Polymers85,7572
Non-polymers1,2732
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3400 Å2
ΔGint-33 kcal/mol
Surface area27480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.820, 118.531, 71.957
Angle α, β, γ (deg.)90.000, 103.060, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 42878.352 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-LSK / methyl 6-[5-[[~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]carbamimidoyl]amino]pentylcarbamoylamino]-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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 123 / 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: 2.39 Å3/Da / Density % sol: 48.49 % / Mosaicity: 0.26 °
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5
Details: PEG 3,350 20%, NaCHOO 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 EIGER X 4M / Detector: PIXEL / Date: Sep 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2→45.26 Å / Num. obs: 45652 / % possible obs: 98.7 % / Redundancy: 3.8 % / Biso Wilson estimate: 27.91 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.055 / Rrim(I) all: 0.112 / Net I/σ(I): 14.4
Reflection shellResolution: 2→2.05 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.629 / Mean I/σ(I) obs: 2 / Num. unique obs: 3074 / CC1/2: 0.679 / Rpim(I) all: 0.376 / Rrim(I) all: 0.737 / % possible all: 91.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimless0.5.32data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4c03

4c03


Resolution: 2→38.53 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 23.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2433 2275 4.99 %
Rwork0.1957 43339 -
obs0.198 45614 98.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 91.99 Å2 / Biso mean: 33.3964 Å2 / Biso min: 13.4 Å2
Refinement stepCycle: final / Resolution: 2→38.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5119 0 92 123 5334
Biso mean--58.06 30.33 -
Num. residues----652
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 16

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.040.34451180.27872470258891
2.04-2.090.30631420.24742715285798
2.09-2.140.26951420.24742663280599
2.14-2.20.28481470.21812758290599
2.2-2.260.24581690.216226722841100
2.26-2.340.24041220.211527712893100
2.34-2.420.22761450.207226882833100
2.42-2.520.26471430.209127162859100
2.52-2.630.21961520.209827562908100
2.63-2.770.25471710.208627132884100
2.77-2.940.29461710.21426872858100
2.94-3.170.25981440.229827332877100
3.17-3.490.27681420.198627572899100
3.49-3.990.24451420.17862704284699
3.99-5.030.17591300.15032730286098
5.03-38.530.2001950.16842806290199
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)
10.0916-0.02730.01950.18010.0740.04140.05780.4176-0.3148-0.0123-0.14330.54920.0805-0.36680.00010.3241-0.0044-0.0670.424-0.01230.4858.180625.5783-12.6642
20.58270.19050.08791.84590.78691.1390.03250.11460.0846-0.0962-0.0476-0.0426-0.08420.09990.00030.1330.029-0.02640.20670.02270.199717.892732.4318-25.8313
30.32190.2747-0.4974-0.078-0.12180.6274-0.1249-0.0196-0.0134-0.1042-0.0093-0.05080.2247-0.0046-0.00040.29450.08060.07260.24450.02940.152912.5153-6.0345-7.4842
40.57940.3715-0.03811.98740.46461.5664-0.029-0.10490.0229-0.0745-0.05940.04560.1379-0.0468-0.00010.21570.05820.00410.2206-0.00460.170913.09544.3421-25.9727
50.625-0.7107-0.26180.83770.40140.2340.13430.11690.0192-0.0664-0.1139-0.1751-0.48190.0702-0.00590.2323-0.00960.02310.18850.00990.200810.022-3.944912.2066
61.0069-0.1572-0.09610.9320.02520.65680.06440.0675-0.1809-0.0763-0.10760.13810.0709-0.1377-0.00010.15850.01330.00470.1619-0.01750.19-1.8461-11.691713.8221
70.37940.25690.14260.524-0.1937-0.0694-0.07410.02010.01190.047-0.00230.0575-0.07080.1142-0.00010.2388-0.03690.04630.2023-0.01530.21471.70255.596418.947
80.5764-0.1668-0.37450.2765-0.4381.09130.41240.0024-0.14740.4209-0.2153-0.2404-0.16040.20120.1120.2745-0.0574-0.11390.25720.04990.279323.022430.1009-4.808
90.24710.1291-0.04040.3850.0210.08890.1450.1410.0633-0.084-0.2188-0.22470.01390.06050.00090.3143-0.1033-0.06230.37090.07080.325616.692420.556410.8622
100.5806-0.475-0.00991.3699-0.2170.83850.0507-0.04050.06650.2096-0.14070.0776-0.0716-0.0155-00.2677-0.08370.00550.2108-0.01910.210310.852318.54718.6168
110.3098-0.13310.02810.2639-0.35260.4537-0.0194-0.18260.3490.0208-0.14430.4191-0.4369-0.3915-0.00090.38890.0055-0.03530.37230.01450.36465.3827.856114.6402
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 43 through 66 )A43 - 66
2X-RAY DIFFRACTION2chain 'A' and (resid 67 through 190 )A67 - 190
3X-RAY DIFFRACTION3chain 'A' and (resid 191 through 234 )A191 - 234
4X-RAY DIFFRACTION4chain 'A' and (resid 235 through 377 )A235 - 377
5X-RAY DIFFRACTION5chain 'B' and (resid 54 through 84 )B54 - 84
6X-RAY DIFFRACTION6chain 'B' and (resid 85 through 153 )B85 - 153
7X-RAY DIFFRACTION7chain 'B' and (resid 154 through 201 )B154 - 201
8X-RAY DIFFRACTION8chain 'B' and (resid 202 through 234 )B202 - 234
9X-RAY DIFFRACTION9chain 'B' and (resid 235 through 253 )B235 - 253
10X-RAY DIFFRACTION10chain 'B' and (resid 254 through 351 )B254 - 351
11X-RAY DIFFRACTION11chain 'B' and (resid 352 through 376 )B352 - 376

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