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- PDB-7uoh: PRMT5/MEP50 crystal structure with MTA and an achiral, class 1, n... -

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Basic information

Entry
Database: PDB / ID: 7uoh
TitlePRMT5/MEP50 crystal structure with MTA and an achiral, class 1, non-atropisomeric inhibitor bound
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / PRMT5 / MTAP / MTA / methyl transferase / collateral lethality / synthetic lethality / fragment-based lead discovery
Function / homology
Function and homology information


positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / peptidyl-arginine methylation / 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 H4R3 methyltransferase activity ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / peptidyl-arginine methylation / 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 H4R3 methyltransferase activity / : / epithelial cell proliferation involved in prostate gland development / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / histone methyltransferase activity / regulation of mitotic nuclear division / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / E-box binding / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / ubiquitin-like ligase-substrate adaptor activity / 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 / p53 binding / transcription corepressor activity / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / 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 / WD domain, G-beta repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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 / Chem-NXF / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsGunn, R.J. / Thomas, N.C. / Lawson, J.D. / Ivetac, A. / Kulyk, S. / Smith, C.R. / Marx, M.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors.
Authors: Smith, C.R. / Aranda, R. / Christensen, J.G. / Engstrom, L.D. / Gunn, R.J. / Ivetac, A. / Ketcham, J.M. / Kuehler, J. / David Lawson, J. / Marx, M.A. / Olson, P. / Thomas, N.C. / Wang, X. / ...Authors: Smith, C.R. / Aranda, R. / Christensen, J.G. / Engstrom, L.D. / Gunn, R.J. / Ivetac, A. / Ketcham, J.M. / Kuehler, J. / David Lawson, J. / Marx, M.A. / Olson, P. / Thomas, N.C. / Wang, X. / Waters, L.M. / Kulyk, S.
History
DepositionApr 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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

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)112,4064
Polymers111,6262
Non-polymers7802
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint-13 kcal/mol
Surface area37780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.638, 138.100, 179.319
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

#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
#3: Chemical ChemComp-NXF / (2M)-2-[(4M)-4-{4-(aminomethyl)-1-oxo-8-[(2R)-oxolan-2-yl]-1,2-dihydrophthalazin-6-yl}-1-methyl-1H-pyrazol-5-yl]-1-benzothiophene-3-carbonitrile


Mass: 482.557 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22N6O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.9 Å3/Da / Density % sol: 57.61 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop
Details: 11 %w/v PEG 4K 0.1 M Na3 Cititrate 5 pH 0.05 M Na Acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 21, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 35686 / % possible obs: 99.7 % / Redundancy: 6.3 % / Biso Wilson estimate: 55.1 Å2 / CC1/2: 0.999 / Rpim(I) all: 0.05 / Net I/σ(I): 13.4
Reflection shellResolution: 2.7→2.75 Å / Num. unique obs: 1727 / CC1/2: 0.79 / Rpim(I) all: 0.49 / % possible all: 97.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7S1R

7s1r


Resolution: 2.7→44.59 Å / SU ML: 0.3919 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.6154
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2321 1787 5.05 %
Rwork0.1967 33597 -
obs0.1985 35384 98.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 78.14 Å2
Refinement stepCycle: LAST / Resolution: 2.7→44.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7332 0 55 12 7399
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00227597
X-RAY DIFFRACTIONf_angle_d0.511410360
X-RAY DIFFRACTIONf_chiral_restr0.04411138
X-RAY DIFFRACTIONf_plane_restr0.00391336
X-RAY DIFFRACTIONf_dihedral_angle_d11.81892738
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.780.40891390.38652394X-RAY DIFFRACTION93.85
2.78-2.860.39431290.32632514X-RAY DIFFRACTION97.13
2.86-2.950.31441200.29872544X-RAY DIFFRACTION97.91
2.95-3.060.36281310.28042569X-RAY DIFFRACTION98.36
3.06-3.180.31151240.26212563X-RAY DIFFRACTION98.28
3.18-3.320.30591180.25272596X-RAY DIFFRACTION99.49
3.32-3.50.25261460.21632571X-RAY DIFFRACTION99.31
3.5-3.720.24761650.19632585X-RAY DIFFRACTION99.57
3.72-40.25751340.1812600X-RAY DIFFRACTION99.45
4-4.410.16581500.15332606X-RAY DIFFRACTION99.67
4.41-5.040.16341340.14052636X-RAY DIFFRACTION99.78
5.04-6.350.20061260.1742671X-RAY DIFFRACTION99.86
6.35-44.590.18921710.15932748X-RAY DIFFRACTION99.42
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)
10.957755830565-0.1177879553960.1086918969261.50073306391-0.09513589917042.24489800239-0.017624848832-0.130957018103-0.201833633828-0.02307797250330.0347207221765-0.1366598077190.4586120480880.4086495719160.004106980312190.7592104001570.1931889279580.03676927616510.607288257938-0.0662194338320.535090123535-27.3466384528-94.0774856623-18.4254240989
22.272151850870.246401176734-0.01335412442072.103417456380.489027467421.497824763430.1168806321340.3173988091160.0913822253006-0.47943250219-0.0584866990652-0.2259683918230.07087880903840.476291579375-0.01702727807710.4998485013120.1203995498060.09863723336360.574048739284-0.03593437121150.459996356186-27.9596662486-78.2973427049-30.7432768449
30.071717962945-0.379954771076-0.2856189067912.022592670181.314799987351.197188898770.192204299735-0.2972531631970.0972001171978-0.2534569199930.0436307202592-0.421264878109-0.4520814858740.66110401834-0.2659035861880.612520483214-0.1370441334650.09787307400390.692748161806-0.01255585388050.569308321564-22.1533726435-56.7309990331-14.2698839011
41.539746454890.7323586200260.3463328840882.015754744610.3498427622541.27815814774-0.006778460690380.108153724370.153292405738-0.1610235000840.0495369081663-0.174374658858-0.6122980035930.356429914168-0.003761066455870.760071851431-0.1156228988030.05999634821960.4318829880470.007592052261560.392235933048-36.8557245553-41.0737695299-15.2297231651
52.18044130934-0.492705724583-2.138661708843.000826152811.90864555452.80201367022-0.175247593564-0.297826700081-0.599007027010.7222291587420.618477231697-0.4257013485840.8323986020171.11198103364-0.3207440509821.741045625880.7893966823270.1269683096371.23210927763-0.1346492015340.939143886139-15.2849869081-116.914332783-28.1237980294
60.816896578552-0.2336570972010.4983807577931.04318938067-0.01596817950790.325909591783-0.03056926027460.17766665034-0.153456494553-0.284788340589-0.0103983450947-0.4919023585070.6308041971840.7855898460010.1006692507641.243749959620.4944871949460.1116548893391.03484274521-0.08333386936840.825091305259-14.5580980823-106.487174199-35.0096065515
71.58340052239-0.248917761764-0.7743957104041.9714033408-0.2602651675131.842316430610.2096192001830.49658862926-0.147060579218-0.439697125727-0.215255572651-0.1508045271040.764848578258-0.1217314638170.001348283393251.323946869860.274005521316-0.02549723923010.786403015552-0.1235669474840.629897294054-31.907218775-104.450061927-47.7785947212
81.95095934773-0.2758484941250.09839761217651.723107004440.07515620732050.929277314645-0.1746448332250.338922432288-0.5858246415820.1772463441770.1792503549840.08775096236831.256013034580.234188492054-0.06531261899081.634195222830.2778257294530.0119555931250.749483623259-0.1612895319570.827969208902-32.7599328409-119.571421267-35.1196803759
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 13 through 131 )AA13 - 1311 - 119
22chain 'A' and (resid 132 through 277 )AA132 - 277120 - 265
33chain 'A' and (resid 278 through 330 )AA278 - 330266 - 318
44chain 'A' and (resid 331 through 637 )AA331 - 637319 - 625
55chain 'B' and (resid 19 through 47 )BD19 - 471 - 29
66chain 'B' and (resid 48 through 175 )BD48 - 17530 - 157
77chain 'B' and (resid 176 through 241 )BD176 - 241158 - 219
88chain 'B' and (resid 242 through 329 )BD242 - 329220 - 302

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