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- PDB-8veo: Crystal structure of PRMT5:MEP50 in complex with MTA -

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Basic information

Entry
Database: PDB / ID: 8veo
TitleCrystal structure of PRMT5:MEP50 in complex with MTA
Components
  • Methylosome protein 50WD repeat-containing protein 77
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / MTAP-null / SAM / MTA / TRANSFERASE / TRANSFERASE-INHIBITOR complex
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 / histone H4R3 methyltransferase activity / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development ...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 / histone H4R3 methyltransferase activity / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / epithelial cell proliferation involved in prostate gland development / histone arginine N-methyltransferase activity / methylosome / protein-arginine N-methyltransferase activity / methyl-CpG binding / positive regulation of mRNA splicing, via spliceosome / : / endothelial cell activation / histone H3 methyltransferase activity / Cul4B-RING E3 ubiquitin ligase complex / regulation of mitotic nuclear division / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / histone methyltransferase activity / E-box binding / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / nuclear receptor coactivator activity / regulation of signal transduction by p53 class mediator / methyltransferase activity / liver regeneration / DNA-templated transcription termination / circadian regulation of gene expression / Regulation of TP53 Activity through Methylation / RMTs methylate histone arginines / protein polyubiquitination / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / chromatin remodeling / protein heterodimerization activity / positive regulation of cell population proliferation / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Protein arginine N-methyltransferase PRMT5 / PRMT5 arginine-N-methyltransferase / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / WD40 repeat, conserved site ...Protein arginine N-methyltransferase PRMT5 / PRMT5 arginine-N-methyltransferase / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
5'-DEOXY-5'-METHYLTHIOADENOSINE / DI(HYDROXYETHYL)ETHER / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.03 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP -Deleted Cancers.
Authors: Cottrell, K.M. / Briggs, K.J. / Whittington, D.A. / Jahic, H. / Ali, J.A. / Davis, C.B. / Gong, S. / Gotur, D. / Gu, L. / McCarren, P. / Tonini, M.R. / Tsai, A. / Wilker, E.W. / Yuan, H. / ...Authors: Cottrell, K.M. / Briggs, K.J. / Whittington, D.A. / Jahic, H. / Ali, J.A. / Davis, C.B. / Gong, S. / Gotur, D. / Gu, L. / McCarren, P. / Tonini, M.R. / Tsai, A. / Wilker, E.W. / Yuan, H. / Zhang, M. / Zhang, W. / Huang, A. / Maxwell, J.P.
History
DepositionDec 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: 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

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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)112,84816
Polymers111,6262
Non-polymers1,22214
Water2,054114
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7450 Å2
ΔGint21 kcal/mol
Surface area37670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.680, 138.880, 178.370
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 2 types, 2 molecules AB

#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 / Fragment: FULL LENGTH
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O14744, type II protein arginine methyltransferase
#2: Protein Methylosome protein 50 / WD repeat-containing protein 77 / 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: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BQA1

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Non-polymers , 5 types, 128 molecules

#3: Chemical ChemComp-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE / 5′-Methylthioadenosine


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 114 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.82 Å3/Da / Density % sol: 56.39 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6
Details: 10% PEG 4000, 0.2M magnesium chloride, 0.1M sodium citrate (pH 6.0)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.03→54.79 Å / Num. obs: 80230 / % possible obs: 98.5 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.019 / Rrim(I) all: 0.049 / Χ2: 0.96 / Net I/σ(I): 18 / Num. measured all: 539109
Reflection shellResolution: 2.03→2.08 Å / % possible obs: 96 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.797 / Num. measured all: 36367 / Num. unique obs: 5690 / CC1/2: 0.914 / Rpim(I) all: 0.338 / Rrim(I) all: 0.867 / Χ2: 0.88 / Net I/σ(I) obs: 2.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.03→54.79 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 38.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2775 4021 5.04 %
Rwork0.2392 --
obs0.2411 79772 97.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.03→54.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7399 0 80 114 7593
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011
X-RAY DIFFRACTIONf_angle_d1.041
X-RAY DIFFRACTIONf_dihedral_angle_d15.9712785
X-RAY DIFFRACTIONf_chiral_restr0.0721145
X-RAY DIFFRACTIONf_plane_restr0.0111348
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.03-2.050.46281340.44762522X-RAY DIFFRACTION95
2.05-2.080.45771300.43142511X-RAY DIFFRACTION96
2.08-2.110.43391480.42542537X-RAY DIFFRACTION96
2.11-2.130.42311260.43722570X-RAY DIFFRACTION97
2.13-2.160.50851390.42662551X-RAY DIFFRACTION97
2.16-2.190.45851400.432558X-RAY DIFFRACTION98
2.19-2.230.46651340.41182614X-RAY DIFFRACTION98
2.23-2.260.38511240.41042605X-RAY DIFFRACTION97
2.26-2.30.38131480.41322556X-RAY DIFFRACTION97
2.3-2.340.44141410.38892600X-RAY DIFFRACTION98
2.34-2.380.37841450.35772588X-RAY DIFFRACTION98
2.38-2.430.34911490.35852599X-RAY DIFFRACTION98
2.43-2.480.35441310.34292598X-RAY DIFFRACTION98
2.48-2.530.36281450.33612619X-RAY DIFFRACTION99
2.53-2.590.33071420.32382605X-RAY DIFFRACTION99
2.59-2.650.3461550.30742585X-RAY DIFFRACTION98
2.65-2.720.35991440.29582631X-RAY DIFFRACTION99
2.72-2.80.36661470.29882606X-RAY DIFFRACTION99
2.8-2.890.33421220.29462652X-RAY DIFFRACTION98
2.89-30.35961260.30822641X-RAY DIFFRACTION99
3-3.120.32471430.27672652X-RAY DIFFRACTION99
3.12-3.260.28531530.25892602X-RAY DIFFRACTION98
3.26-3.430.25451260.24762622X-RAY DIFFRACTION98
3.43-3.650.28151440.23752652X-RAY DIFFRACTION98
3.65-3.930.28191430.20932618X-RAY DIFFRACTION98
3.93-4.320.21121260.1742653X-RAY DIFFRACTION98
4.32-4.950.18921520.1492698X-RAY DIFFRACTION99
4.95-6.230.19971400.15982690X-RAY DIFFRACTION98
6.24-54.790.17421240.15682816X-RAY DIFFRACTION97
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)
10.015-0.0256-0.00080.02670.01890.0458-0.0549-0.1115-0.0272-0.12150.0206-0.01510.20550.1401-00.4360.1250.0140.3996-0.03390.376522.9134-93.5428-17.7416
20.0122-0.00680.01140.0641-0.00440.01650.09890.0324-0.0048-0.1842-0.05280.06140.03480.11320.00080.32280.09420.08440.368-0.01720.315525.896-77.9356-32.8302
30.00680.0005-0.00460.0035-0.00380.00240.020.0128-0.01990.0289-0.0038-0.057-0.03310.1327-00.4412-0.0610.06260.5131-0.03210.452629.8942-57.0153-14.4076
40.0463-0.01560.04090.0416-0.12270.6055-0.02690.0741-0.18550.146-0.06290.0435-0.70350.0708-0.03130.2327-0.24090.10030.26970.0430.233819.1202-36.5689-11.3121
50.02940.03740.14040.03780.16250.6424-0.04290.0643-0.1509-0.147-0.04720.0558-0.2794-0.0527-0.05660.20330.00260.04030.28510.01760.31568.6517-49.08-21.5161
60.00420.0019-0.00060.0043-0.00370.00410.0164-0.00540.0013-0.0177-0.0124-0.01580.00650.0179-0.00030.87980.32670.06430.6429-0.0460.611436.0975-117.6968-28.1964
70.0192-0.00280.00380.02890.01560.0241-0.042-0.0097-0.001-0.0722-0.0052-0.09170.25170.202700.78030.34360.05960.6443-0.01090.495635.0827-106.5684-37.1208
8-0.0011-0.0054-0.00440.01150.00250.00280.03480.0671-0.00010.0004-0.02060.02310.051-0.032900.86660.16750.02130.503-0.04380.468615.4321-106.9131-46.1821
90.0024-0.00420.00380.0116-0.00740.0042-0.02880.0009-0.0403-0.02470.0268-0.0130.0726-0.008701.07120.2699-0.02250.4659-0.07770.520120.146-121.367-34.668
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 13 through 149 )
2X-RAY DIFFRACTION2chain 'A' and (resid 150 through 277 )
3X-RAY DIFFRACTION3chain 'A' and (resid 278 through 330 )
4X-RAY DIFFRACTION4chain 'A' and (resid 331 through 522 )
5X-RAY DIFFRACTION5chain 'A' and (resid 523 through 637 )
6X-RAY DIFFRACTION6chain 'B' and (resid 19 through 47 )
7X-RAY DIFFRACTION7chain 'B' and (resid 48 through 196 )
8X-RAY DIFFRACTION8chain 'B' and (resid 197 through 259 )
9X-RAY DIFFRACTION9chain 'B' and (resid 260 through 328 )

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