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- PDB-6nt2: type 1 PRMT in complex with the inhibitor GSK3368715 -

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Basic information

Entry
Database: PDB / ID: 6nt2
Titletype 1 PRMT in complex with the inhibitor GSK3368715
ComponentsProtein arginine N-methyltransferase 1
KeywordsANTITUMOR PROTEIN / inhibitor / cmplex / methyl transferase / arginine
Function / homology
Function and homology information


GATOR1 complex binding / positive regulation of hemoglobin biosynthetic process / protein-arginine omega-N monomethyltransferase activity / N-methyltransferase activity / peptidyl-arginine methylation / regulation of BMP signaling pathway / type I protein arginine methyltransferase / protein-arginine omega-N asymmetric methyltransferase activity / regulation of megakaryocyte differentiation / protein methyltransferase activity ...GATOR1 complex binding / positive regulation of hemoglobin biosynthetic process / protein-arginine omega-N monomethyltransferase activity / N-methyltransferase activity / peptidyl-arginine methylation / regulation of BMP signaling pathway / type I protein arginine methyltransferase / protein-arginine omega-N asymmetric methyltransferase activity / regulation of megakaryocyte differentiation / protein methyltransferase activity / protein methylation / 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 / cellular response to methionine / protein-arginine N-methyltransferase activity / methylosome / negative regulation of JNK cascade / S-adenosyl-L-methionine binding / methyl-CpG binding / positive regulation of p38MAPK cascade / histone H2AQ104 methyltransferase activity / cardiac muscle tissue development / Maturation of nucleoprotein / mitogen-activated protein kinase p38 binding / histone methyltransferase activity / negative regulation of megakaryocyte differentiation / positive regulation of double-strand break repair via homologous recombination / positive regulation of TORC1 signaling / RNA splicing / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of erythrocyte differentiation / positive regulation of translation / methyltransferase activity / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / protein homooligomerization / RMTs methylate histone arginines / neuron projection development / Estrogen-dependent gene expression / in utero embryonic development / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / viral protein processing / chromatin remodeling / lysosomal membrane / positive regulation of cell population proliferation / DNA damage response / regulation of DNA-templated transcription / enzyme binding / RNA binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 / : / Arginine methyltransferase oligomerization subdomain / Methyltransferase domain 25 / Methyltransferase domain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / Distorted Sandwich / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Mainly Beta
Similarity search - Domain/homology
2,3-DIHYDROXY-1,4-DITHIOBUTANE / Chem-KZS / S-ADENOSYL-L-HOMOCYSTEINE / Protein arginine N-methyltransferase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsConcha, N.O.
CitationJournal: Cancer Cell / Year: 2019
Title: Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.
Authors: Fedoriw, A. / Rajapurkar, S.R. / O'Brien, S. / Gerhart, S.V. / Mitchell, L.H. / Adams, N.D. / Rioux, N. / Lingaraj, T. / Ribich, S.A. / Pappalardi, M.B. / Shah, N. / Laraio, J. / Liu, Y. / ...Authors: Fedoriw, A. / Rajapurkar, S.R. / O'Brien, S. / Gerhart, S.V. / Mitchell, L.H. / Adams, N.D. / Rioux, N. / Lingaraj, T. / Ribich, S.A. / Pappalardi, M.B. / Shah, N. / Laraio, J. / Liu, Y. / Butticello, M. / Carpenter, C.L. / Creasy, C. / Korenchuk, S. / McCabe, M.T. / McHugh, C.F. / Nagarajan, R. / Wagner, C. / Zappacosta, F. / Annan, R. / Concha, N.O. / Thomas, R.A. / Hart, T.K. / Smith, J.J. / Copeland, R.A. / Moyer, M.P. / Campbell, J. / Stickland, K. / Mills, J. / Jacques-O'Hagan, S. / Allain, C. / Johnston, D. / Raimondi, A. / Porter Scott, M. / Waters, N. / Swinger, K. / Boriack-Sjodin, A. / Riera, T. / Shapiro, G. / Chesworth, R. / Prinjha, R.K. / Kruger, R.G. / Barbash, O. / Mohammad, H.P.
History
DepositionJan 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 24, 2019Group: Data collection / Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.3Nov 6, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms / struct_ncs_dom_lim
Item: _chem_comp.mon_nstd_flag / _chem_comp.type ..._chem_comp.mon_nstd_flag / _chem_comp.type / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein arginine N-methyltransferase 1
D: Protein arginine N-methyltransferase 1
B: Protein arginine N-methyltransferase 1
C: Protein arginine N-methyltransferase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,32236
Polymers170,0464
Non-polymers5,27632
Water11,962664
1
A: Protein arginine N-methyltransferase 1
D: Protein arginine N-methyltransferase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,72219
Polymers85,0232
Non-polymers2,69917
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Protein arginine N-methyltransferase 1
C: Protein arginine N-methyltransferase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,60017
Polymers85,0232
Non-polymers2,57715
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)174.150, 174.150, 142.350
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12D
22C

NCS domain segments:

Refine code: 4

Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111PROPROSERSERAA42 - 4942 - 49
211PROPROSERSERBC42 - 4942 - 49
121SERSERARGARGAA56 - 37156 - 371
221SERSERARGARGBC56 - 37156 - 371
112PROPROSERSERDB42 - 4942 - 49
212PROPROSERSERCD42 - 4942 - 49
122SERSERARGARGDB56 - 37156 - 371
222SERSERARGARGCD56 - 37156 - 371

NCS ensembles :
ID
1
2

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.99955, -0.029967, -0.001397), (-0.029966, 0.99955, -0.001131), (0.00143, -0.001089, -0.999998)2.27898, 0.02178, 31.58835
3given(-0.999739, -0.022509, 0.003992), (-0.022524, 0.999739, -0.003891), (-0.003903, -0.00398, -0.999985)2.06152, -0.0443, 31.70713

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Components

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Protein , 1 types, 4 molecules ADBC

#1: Protein
Protein arginine N-methyltransferase 1 / Histone-arginine N-methyltransferase PRMT1 / Interferon receptor 1-bound protein 4


Mass: 42511.551 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT1, HMT2, HRMT1L2, IR1B4 / Production host: Escherichia coli (E. coli)
References: UniProt: Q99873, type I protein arginine methyltransferase

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Non-polymers , 5 types, 696 molecules

#2: Chemical
ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H20N6O5S
#3: Chemical
ChemComp-KZS / N~1~-({5-[4,4-bis(ethoxymethyl)cyclohexyl]-1H-pyrazol-4-yl}methyl)-N~1~,N~2~-dimethylethane-1,2-diamine / GSK3368715


Mass: 366.541 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H38N4O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical...
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 23 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 664 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.17 Å3/Da / Density % sol: 61.24 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: SAH and inhibitor were added to PRMT1 to a final concentration of 1.5mM each (3% DMSO). The complex was incubated at 4deg C before crystallization. 1uL protein-ligand complex was mixed with ...Details: SAH and inhibitor were added to PRMT1 to a final concentration of 1.5mM each (3% DMSO). The complex was incubated at 4deg C before crystallization. 1uL protein-ligand complex was mixed with 1 uL of reservoir solution containing 0.3M sodium formate, 0.1M HEPES, 8% PEG 10,000, pH 6.5, and 0.2 uL 30% sodium dextran sulfate Mr=5,000). The droplets were incubated against 500uL reservoir solution for 1-2 days before crystals were observed.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 9, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.48→38.94 Å / Num. obs: 77777 / % possible obs: 100 % / Redundancy: 9.9 % / CC1/2: 0.996 / Rmerge(I) obs: 0.179 / Rpim(I) all: 0.06 / Rrim(I) all: 0.189 / Net I/σ(I): 12.7
Reflection shellResolution: 2.48→2.51 Å / Redundancy: 10.1 % / Rmerge(I) obs: 0.961 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 57208 / CC1/2: 0.81 / Rpim(I) all: 0.319 / Rrim(I) all: 1.013 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.48→38.94 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.917 / SU B: 14.089 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.332 / ESU R Free: 0.227 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22169 3909 5 %RANDOM
Rwork0.19026 ---
obs0.19183 73795 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 22.078 Å2
Baniso -1Baniso -2Baniso -3
1-0.54 Å2-0 Å2-0 Å2
2--0.54 Å2-0 Å2
3----1.08 Å2
Refinement stepCycle: 1 / Resolution: 2.48→38.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10732 0 354 664 11750
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0211751
X-RAY DIFFRACTIONr_bond_other_d0.0020.0210783
X-RAY DIFFRACTIONr_angle_refined_deg1.1961.97215908
X-RAY DIFFRACTIONr_angle_other_deg0.8513.00525042
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.93851388
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.50623.978548
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.001151994
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6551556
X-RAY DIFFRACTIONr_chiral_restr0.0670.21738
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212762
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022494
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.412.0865462
X-RAY DIFFRACTIONr_mcbond_other0.412.0865461
X-RAY DIFFRACTIONr_mcangle_it0.7683.1256844
X-RAY DIFFRACTIONr_mcangle_other0.7683.1256845
X-RAY DIFFRACTIONr_scbond_it0.3262.2026289
X-RAY DIFFRACTIONr_scbond_other0.3242.2026289
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.5953.2569053
X-RAY DIFFRACTIONr_long_range_B_refined3.08723.36112631
X-RAY DIFFRACTIONr_long_range_B_other3.01523.19912535
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A5090medium positional0.250.5
22B5135medium positional0.290.5
11D5090medium thermal0.952
22C5135medium thermal0.822
LS refinement shellResolution: 2.48→2.544 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.281 279 -
Rwork0.26 5379 -
obs--100 %
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)
10.5735-0.57810.07841.633-0.18740.68890.00790.0514-0.0347-0.0486-0.0040.00720.10460.0069-0.0040.0189-0.00060.00240.0221-0.00990.00664.432834.961535.307
20.55310.39660.031.5030.19160.75170.0018-0.0407-0.04780.0432-0.00020.03210.0794-0.0361-0.00160.01090.00060.0060.02890.01240.0188-3.239134.9023-3.7733
30.7266-0.4509-0.10941.51870.03680.90410.01660.05990.0416-0.0612-0.03570.0168-0.0699-0.04060.0190.01920.0026-0.00470.01880.00770.0069-4.673249.9557-34.2822
40.72960.4582-0.06211.5474-0.13960.84110.0279-0.04790.04060.0892-0.0186-0.0024-0.07720.0077-0.00920.0187-0.00770.00250.0192-0.00820.00475.431450.182165.8117
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 371
2X-RAY DIFFRACTION2B42 - 371
3X-RAY DIFFRACTION3C42 - 371
4X-RAY DIFFRACTION4D42 - 371

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