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- PDB-8vex: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide ... -

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Basic information

Entry
Database: PDB / ID: 8vex
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 28
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / MTAP-null / SAM / MTA / inhibitor / MTA-cooperative / 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 / peptidyl-arginine methylation / protein-arginine omega-N symmetric methyltransferase activity / 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 arginine N-methyltransferase activity ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / peptidyl-arginine methylation / protein-arginine omega-N symmetric methyltransferase activity / 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 arginine N-methyltransferase activity / epithelial cell proliferation involved in prostate gland development / histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / histone H3R8 methyltransferase activity / histone H3R26 methyltransferase activity / histone H4R3 methyltransferase activity / histone H3K37 methyltransferase activity / histone H4K12 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / histone H2A Q104 methyltransferase activity / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / regulation of ERK1 and ERK2 cascade / spliceosomal snRNP assembly / ribonucleoprotein complex binding / : / 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 / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / 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. / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / 5'-DEOXY-5'-METHYLTHIOADENOSINE / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.79 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
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)112,4557
Polymers111,6262
Non-polymers8295
Water1,06359
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6390 Å2
ΔGint-45 kcal/mol
Surface area37020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.470, 136.350, 177.690
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 / 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, 64 molecules

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


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-A1AAR / N-(6-amino-5-methylpyridin-3-yl)-2-[(2R,5S)-2-(4-hydroxyphenyl)-5-methylpiperidin-1-yl]-2-oxoacetamide


Mass: 368.430 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N4O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 2.7 Å3/Da / Density % sol: 54.42 %
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: BL18U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.79→45.2 Å / Num. obs: 30399 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.037 / Rrim(I) all: 0.095 / Χ2: 0.99 / Net I/σ(I): 15.1
Reflection shellResolution: 2.79→2.94 Å / % possible obs: 99.8 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.763 / Num. measured all: 28685 / Num. unique obs: 4354 / CC1/2: 0.945 / Rpim(I) all: 0.32 / Rrim(I) all: 0.829 / Χ2: 0.94 / Net I/σ(I) obs: 2.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
Aimlessdata scaling
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.79→45.2 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.926 / SU B: 75.29 / SU ML: 0.571 / Cross valid method: THROUGHOUT / ESU R Free: 0.391 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26972 1497 4.9 %RANDOM
Rwork0.22641 ---
obs0.22861 28776 99.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 88.96 Å2
Baniso -1Baniso -2Baniso -3
1-7.01 Å20 Å2-0 Å2
2---0.8 Å20 Å2
3----6.21 Å2
Refinement stepCycle: 1 / Resolution: 2.79→45.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7338 0 55 59 7452
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0137609
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176856
X-RAY DIFFRACTIONr_angle_refined_deg1.4371.64610370
X-RAY DIFFRACTIONr_angle_other_deg1.1261.57515936
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7135928
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.90122.219401
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.581151224
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5161548
X-RAY DIFFRACTIONr_chiral_restr0.0510.2973
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.028512
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021630
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_it1.2934.1233706
X-RAY DIFFRACTIONr_mcbond_other1.2934.1233705
X-RAY DIFFRACTIONr_mcangle_it2.2156.1854630
X-RAY DIFFRACTIONr_mcangle_other2.2156.1854631
X-RAY DIFFRACTIONr_scbond_it1.1444.2663902
X-RAY DIFFRACTIONr_scbond_other1.1444.2673903
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.9826.3545739
X-RAY DIFFRACTIONr_long_range_B_refined4.53347.5338253
X-RAY DIFFRACTIONr_long_range_B_other4.53247.548254
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.79→2.862 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.442 98 -
Rwork0.458 2082 -
obs--99.18 %
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)
12.0054-0.15930.22132.4498-0.02762.8628-0.0227-0.1341-0.0547-0.00280.003-0.15810.32080.35680.01960.8880.09820.07040.25510.0010.021423.1394-90.9609-18.9003
22.0731-0.7035-1.05692.60451.42672.2220.05890.32270.1887-0.44830.1117-0.6211-0.38840.575-0.17061.1930.01260.09020.45130.05230.191728.5336-72.7933-30.2328
32.17280.59350.87792.65380.73631.5772-0.09610.18710.22-0.0980.0937-0.2451-0.49330.30170.00241.1813-0.11990.04250.24920.01140.061419.6353-36.2884-10.4347
44.01762.13060.58782.80780.47462.1967-0.01550.3459-0.1512-0.22440.10190.1113-0.3590.2332-0.08640.90240.01040.00660.20140.00970.04128.6958-48.0206-21.2386
50.4887-1.3615-1.98067.20817.38069.99490.15970.1579-0.04110.20090.044-0.61120.4949-0.4039-0.20380.9550.20050.04420.64850.03410.598233.5372-112.2334-27.1312
62.1963-1.08730.98152.5734-0.91832.9350.06710.1295-0.141-0.2401-0.0065-0.33770.50770.9221-0.06061.40320.29390.07990.6098-0.09920.192135.2218-104.2164-39.276
71.17551.44750.06521.8191-0.22593.1991-0.25550.27050.0878-0.43750.39260.15810.7296-1.1284-0.13711.39370.1033-0.0350.8264-0.10560.53514.7638-105.9006-46.8831
82.6963-1.08820.17983.2154-0.37711.0017-0.02860.4345-0.4715-0.05370.14650.42310.7840.1366-0.11791.70970.17910.03730.4204-0.08110.298220.0609-118.8804-34.5736
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A13 - 162
2X-RAY DIFFRACTION2A163 - 310
3X-RAY DIFFRACTION3A311 - 522
4X-RAY DIFFRACTION4A523 - 637
5X-RAY DIFFRACTION5B28 - 55
6X-RAY DIFFRACTION6B56 - 201
7X-RAY DIFFRACTION7B202 - 252
8X-RAY DIFFRACTION8B253 - 328

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