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- PDB-9n3o: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide ... -

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Basic information

Entry
Database: PDB / ID: 9n3o
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 14
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / inhibitor / MTA-cooperative / MTAP-null / 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 / 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 / cytoplasm / cytosol
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. / 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 / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase 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: 2.37 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion.
Authors: Cottrell, K.M. / Briggs, K.J. / Tsai, A. / Tonini, M.R. / Whittington, D.A. / Gong, S. / Liang, C. / McCarren, P. / Zhang, M. / Zhang, W. / Huang, A. / Maxwell, J.P.
History
DepositionJan 31, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)113,14317
Polymers111,6262
Non-polymers1,51715
Water6,431357
1
A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules


Theoretical massNumber of molelcules
Total (without water)452,57068
Polymers446,5048
Non-polymers6,06660
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area47760 Å2
ΔGint3 kcal/mol
Surface area131660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.760, 137.200, 176.840
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

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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
Details: N-terminal Flag tag / 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 / Methylosome protein ...MEP-50 / Androgen receptor cofactor p44 / WD repeat-containing protein 77 / Methylosome protein WDR77 / p44/Mep50


Mass: 37862.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: N-terminal His-8 tag / 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 , 6 types, 372 molecules

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


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S
#4: Chemical ChemComp-A1BV4 / N-(4-amino-1H-pyrazolo[4,3-c]pyridin-7-yl)-2-[(2R,5S)-2-(1,3-benzothiazol-5-yl)-5-methylpiperidin-1-yl]-2-oxoacetamide


Mass: 435.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21N7O2S / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


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


Mass: 18.015 Da / Num. of mol.: 357 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.76 Å3/Da / Density % sol: 55.51 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6
Details: 10% PEG 4000. 0.1 M sodium citrate (pH 6.0), 0.2 M magnesium chloride, 1 mM methylthioadenosine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 0.97628 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97628 Å / Relative weight: 1
ReflectionResolution: 2.37→46.06 Å / Num. obs: 50480 / % possible obs: 100 % / Redundancy: 7.4 % / Biso Wilson estimate: 48.73 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.07 / Net I/σ(I): 17.4
Reflection shellResolution: 2.37→2.45 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.779 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 4561 / CC1/2: 0.849 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.37→46.06 Å / SU ML: 0.344 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.5077
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2274 2507 4.97 %
Rwork0.1942 47963 -
obs0.1959 50470 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60.71 Å2
Refinement stepCycle: LAST / Resolution: 2.37→46.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7353 0 99 357 7809
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00187681
X-RAY DIFFRACTIONf_angle_d0.516210450
X-RAY DIFFRACTIONf_chiral_restr0.04441143
X-RAY DIFFRACTIONf_plane_restr0.00391350
X-RAY DIFFRACTIONf_dihedral_angle_d12.93562788
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.37-2.420.33931570.3112595X-RAY DIFFRACTION99.93
2.42-2.460.37071230.29142638X-RAY DIFFRACTION99.93
2.46-2.520.41591560.29232614X-RAY DIFFRACTION99.89
2.52-2.580.36531330.28342622X-RAY DIFFRACTION99.96
2.58-2.640.32021580.26662629X-RAY DIFFRACTION99.93
2.64-2.710.28511280.25332651X-RAY DIFFRACTION99.93
2.71-2.790.27561390.22812667X-RAY DIFFRACTION100
2.79-2.880.29371470.22212617X-RAY DIFFRACTION99.96
2.88-2.990.26961420.23022658X-RAY DIFFRACTION99.96
2.99-3.110.24071200.22392672X-RAY DIFFRACTION100
3.11-3.250.25841300.21022640X-RAY DIFFRACTION99.96
3.25-3.420.23111290.19812695X-RAY DIFFRACTION99.96
3.42-3.630.20191570.18442641X-RAY DIFFRACTION99.96
3.63-3.910.21731330.17962669X-RAY DIFFRACTION100
3.91-4.30.17021330.15682699X-RAY DIFFRACTION99.96
4.31-4.930.17741320.15172711X-RAY DIFFRACTION100
4.93-6.210.18211470.17252715X-RAY DIFFRACTION100
6.21-46.060.21171430.17652830X-RAY DIFFRACTION99.5
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)
12.02471221602-0.09569055725150.2739162000222.04423574130.0518972918882.28194309258-0.00458648288527-0.0400246881836-0.04110628777840.0632024368817-0.0444544946039-0.04928261661830.2184952471970.3723790498220.04087720719650.3591331393010.1008171898020.01795183087290.428326186149-0.04247938698910.29282492882522.9769099743-91.6877206484-17.7696064263
22.17912226931-0.5233373390680.3612468032842.525785320970.4543842875051.644827685260.1312479641430.271582281810.150442780345-0.493602984411-0.104474899065-0.207496434722-0.07273294473150.480638593677-0.03856335529790.4325789300880.0495849512490.09936815156330.5475756755940.0107829232020.3901694332625.9502667006-76.5872483431-33.2343513203
30.0875556471786-0.598560662955-0.335330075363.667079230572.104414471911.41224232603-0.0450727620149-0.0475512557746-0.00223263854504-0.2170567453480.205471320247-0.427202262459-0.1378893195160.614421434942-0.2986873313130.460902820695-0.09982405596790.05665657934610.686409419531-0.009622863817160.47038066494729.9313404497-56.3573680524-14.0944297526
41.372016952850.6440856772230.4173690545191.544651717030.5675326546621.595624535460.005394220113560.1385174860770.113662622328-0.126945088280.016680469187-0.0686358734749-0.4832018709090.233766673734-0.02426444105990.438229661046-0.05493352367030.04281481132460.3880215250540.0283410526860.31406700407115.280294911-40.588776457-15.1422113173
52.54934052873-1.5759354427-0.7020030960083.003211542651.771799359921.079523257370.00301397519320.0290784277346-0.3683863069370.4524920685080.117579871517-0.3617122588861.119771205750.706148365861-0.1393040275651.003837718840.486534858569-0.0134113271830.806387220197-0.06917197987160.62111585803736.5574915719-114.709455198-25.7859817682
60.6904216063280.3270712186250.8506149768181.36969760137-0.2342364072371.95033991360.1553205616920.181158900549-0.0102377388414-0.328610277971-0.0906909420783-0.4001689559040.465444668240.739921106622-0.07297440289650.6839164602810.3595776108170.0570715927870.841984688068-0.06989437520720.47992465642534.7630628224-102.38788642-40.4026604611
71.767181086661.76477444509-2.4835396932.86614795123-2.342345203853.615594706440.05485294223370.595242147966-0.104963604602-0.5568021816720.02907755386480.258522004870.397571923531-0.292880981781-0.06649669140880.811793795920.220018640479-0.122619355410.649620672605-0.1375291699940.51509024485116.3554888721-106.361845356-45.258344043
81.20633587160.4455340352780.8049629888021.424794640140.1411917248512.164679987230.03887085455210.280911226668-0.588363724601-0.0299217149156-0.004501583266070.1317319367761.013357477290.2314136058760.04276694719371.075034012140.26752140252-0.07607168805510.570722809688-0.1627468838620.62606956639520.9518265006-120.402191574-33.670372119
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 156 )AA13 - 1561 - 144
22chain 'A' and (resid 157 through 277 )AA157 - 277145 - 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 26 through 82 )BB26 - 821 - 57
66chain 'B' and (resid 83 through 196 )BB83 - 19658 - 171
77chain 'B' and (resid 197 through 263 )BB197 - 263172 - 238
88chain 'B' and (resid 264 through 328 )BB264 - 328239 - 303

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