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- PDB-9n3q: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide ... -

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Basic information

Entry
Database: PDB / ID: 9n3q
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 51
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: 2.54 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
C: Protein arginine N-methyltransferase 5
D: Methylosome protein 50
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,9229
Polymers223,2524
Non-polymers1,6705
Water1,49583
1
A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
C: Protein arginine N-methyltransferase 5
D: Methylosome protein 50
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)449,84418
Polymers446,5048
Non-polymers3,34010
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area38150 Å2
ΔGint-68 kcal/mol
Surface area134870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.410, 136.450, 178.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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Protein , 2 types, 4 molecules ACBD

#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.: 2 / 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.: 2
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 , 4 types, 88 molecules

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


Mass: 297.334 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H15N5O3S
#4: Chemical ChemComp-A1BV2 / N-(6-amino-5-methylpyridin-3-yl)-2-{(2R,5S)-5-methyl-2-[2-(1-methylpiperidin-4-yl)-1,3-benzothiazol-5-yl]piperidin-1-yl}-2-oxoacetamide


Mass: 506.663 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H34N6O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 2.65 Å3/Da / Density % sol: 53.64 %
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 methylthioadenonsine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 6, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→48.71 Å / Num. obs: 44771 / % possible obs: 55.6 % / Redundancy: 13.4 % / Biso Wilson estimate: 39.07 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.183 / Net I/σ(I): 11.5
Reflection shellResolution: 2.54→2.63 Å / Redundancy: 11.6 % / Rmerge(I) obs: 0.985 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 256 / CC1/2: 0.739 / % possible all: 2.8

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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: 2.54→48.71 Å / SU ML: 0.3039 / Cross valid method: FREE R-VALUE / σ(F): 1.99 / Phase error: 29.2706
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2667 2161 4.83 %
Rwork0.232 42567 -
obs0.2337 44728 56.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.64 Å2
Refinement stepCycle: LAST / Resolution: 2.54→48.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14651 0 116 83 14850
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002615168
X-RAY DIFFRACTIONf_angle_d0.632820670
X-RAY DIFFRACTIONf_chiral_restr0.04542271
X-RAY DIFFRACTIONf_plane_restr0.00482668
X-RAY DIFFRACTIONf_dihedral_angle_d14.81375475
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.54-2.60.463440.3845114X-RAY DIFFRACTION2.28
2.6-2.660.4456130.3578295X-RAY DIFFRACTION5.92
2.66-2.730.4029330.3035505X-RAY DIFFRACTION10.32
2.73-2.820.3759420.3132766X-RAY DIFFRACTION15.55
2.82-2.910.3435470.28561099X-RAY DIFFRACTION21.89
2.91-3.010.333950.30091516X-RAY DIFFRACTION30.92
3.01-3.130.33231230.29092291X-RAY DIFFRACTION45.94
3.13-3.270.28861480.29662905X-RAY DIFFRACTION58.53
3.27-3.450.31581700.28723510X-RAY DIFFRACTION70.11
3.45-3.660.27892370.25844137X-RAY DIFFRACTION83.06
3.66-3.940.29992170.254878X-RAY DIFFRACTION96.64
3.94-4.340.26042470.22485043X-RAY DIFFRACTION99.92
4.34-4.970.26132540.19735080X-RAY DIFFRACTION99.96
4.97-6.260.22992680.20345110X-RAY DIFFRACTION99.93
6.26-48.710.21172630.19365318X-RAY DIFFRACTION99.86
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)
10.004458949403180.02250050588720.007787027423830.01469752608160.0170215937306-0.0007216917632620.005028743235250.01972609544190.0670314312857-0.02124960903390.0345110437816-0.0404948798935-0.03731571956820.1951265518760.02692877420220.107699568462-0.559977292506-0.1225973721860.0932985270102-0.2206295274230.16553922831921.300596318224.981045143462.3554335491
20.02757883036860.0150691408039-0.00791580643315-0.00319745909585-0.002355643060880.00306965688680.0147961927612-0.0619635727205-0.01008676988360.06692704277180.07105758148-0.08745328567290.02688925252050.1077081429980.02475450316910.184367819648-0.230061798295-0.2567434167630.280501652356-0.1128170017770.14380873621325.51966606659.9863903364377.9642060812
30.02637019338280.001064082935320.006157664175170.00114360091136-0.005414084752650.002495119727040.0416443394894-0.004207141139560.01433625394710.0203786969275-0.00269974463719-0.0451032006471-0.01675680533540.1019328419510.04958330153850.03567139095270.0735668216337-0.1386241313830.1317596159330.01223860906840.08892518965231.059287177-9.9766948305258.8142086391
40.05082476938530.0101302639279-0.03662426474660.0424330757103-0.07277977678050.322632188466-0.00944605689555-0.199743554571-0.159421571520.0760952988683-0.0405569731561-0.2637850363340.4505011092880.323345571706-0.05137290905810.1195683665090.297259234583-0.241704048985-0.1608707461340.289615310771-0.19405995320817.5710540892-26.706855026259.7531054058
50.003883365316540.00062559176165-0.005457215139040.003507059005780.00813511653650.0293364393460.03609787164890.0196159374267-0.0007200454383770.01333905755060.018862448215-0.00276039536972-0.01161246863250.01207449688990.01542649302560.484506784153-0.391484411321-0.04284371740220.384543060019-0.2160764045780.51660755762632.905717022249.286236439870.9335970607
60.02015730130840.02868673755070.01235067622320.01826283191720.01714147098950.0256700396450.0398727157821-0.002731399723350.05623270092820.0220252419880.0332518596787-0.102172781257-0.03382579195120.0359532937350.04842437166080.407184783048-0.413120418752-0.2375399060660.508062443734-0.3244105006570.27181691828532.105573248636.539886058485.4141119604
7-0.0007514463565220.00657925637868-0.001566791001870.0048193167947-0.003585117197480.004896335818650.0188499665423-0.05504906228010.0022140087290.0552451304680.0316899052923-0.0001799346420160.01884991102310.001701786321990.005998122382410.535065476149-0.193854633414-0.0791251520770.386574998295-0.1918704222340.28572644974513.436141527239.32794336590.0906190249
80.00655146047918-0.00272277895787-0.002343475477050.005401395571680.002109950193150.00411123074949-0.0460222133551-0.06074104006770.07501298526820.01108260335570.015895993176-0.0222722788621-0.0419327577087-0.03061509552910.009063120694970.498903878748-0.240721757027-0.02672891640210.301932256558-0.2055384627560.36653305936716.889564941553.541481589178.5199428456
90.0112580816956-0.00985768994036-0.01101812429230.00771386303730.01707548090580.0296848785244-0.0233145573802-0.0900050175743-0.003848314147010.02485324911890.0625698333527-0.05621667364090.07210939429520.2280778687650.0369968286259-0.1161127939510.2116941902840.09710779260750.216502914376-0.1277014619580.15442883075924.7758858303-21.573472680526.7368382986
100.04146293656650.00318593468493-0.00780651599894-0.001955766223370.005104439449770.0341543324920.05805602662860.006194444005650.03813991887-0.08643396632460.0477615115628-0.0826144571335-0.02540867509970.1607245342960.07623983919440.11916862121-0.03205133400940.225626080490.188148009815-0.08135202210320.067494874251526.539280428-6.0155501929611.0210892379
110.01725883350770.01151237722330.0002595143041730.002008682017820.00185826004153-0.001661522416490.0217779773351-0.0009462972759980.003003501896080.0180239510984-0.0187884585967-0.0454676635498-0.01593915993510.05743751261750.004665277683870.0891431941034-0.1816669853190.04714437266710.264858302035-0.03361704593040.16850694035529.173841894914.601060279630.3167904893
12-0.04601243165170.01762207720040.0138113774330.02562162500570.02894924973330.2649605930290.02761674472050.02810495359260.386813676808-0.040200166259-0.0132630670515-0.296923463847-0.5086530604130.3293722521470.0767788266742-0.12221660815-0.7866809062550.0514984812162-0.820135135569-0.0223936803116-0.56773906456713.061641911129.208205025429.3754563487
130.009336906954130.00104485128601-0.004232970220740.0016456997377-0.0008598919901060.00907208152340.0229271056203-0.01135738515730.00484698536570.0216952881924-0.0177276539511-0.01342087103660.03108976040340.0252857102053-0.006312041719210.5773327327250.4262823485670.1521968743650.541743271286-0.1346587349240.54296241765140.3670322395-43.352956305717.9844291715
140.013004366711-0.0129377609875-0.01366143442320.002445050542730.008989392057080.0148885141725-0.02740038567850.0116397791236-0.03831225130660.005107519978390.00530521589251-0.05351226857760.05183666229390.0697846606813-0.01450493750950.2848396566160.3812361539950.1527146935430.412330971648-0.153580964070.21645538822337.3121654343-30.90873615833.52854303411
150.03310081574330.01454904108120.002937618955150.00646308467227-0.002317895148290.00690488127461-0.007450607717660.1034924881490.0026154445653-0.0500990569532-0.02020634244230.02812164311210.00387622801878-0.00319648784535-0.004070837555780.389516085910.1666235229990.09397141617820.245235178092-0.0615932746320.27403270393419.2975711455-36.7085782019-1.01424170792
160.00145281606025-0.002524312087180.004051095396520.00509193746886-0.004736778213570.00417366057536-0.0137459934616-0.0101176929198-0.0157007028036-0.01905554607380.0547208297361-0.003003284563270.04618372250780.0274954276182-6.12714605738E-60.6524309983720.1942971530690.01245957786940.36559968032-0.06299726180580.35912206284525.293274226-50.131280273510.3992612714
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 27 through 82 )BB27 - 821 - 56
66chain 'B' and (resid 83 through 196 )BB83 - 19657 - 170
77chain 'B' and (resid 197 through 263 )BB197 - 263171 - 234
88chain 'B' and (resid 264 through 328 )BB264 - 328235 - 299
99chain 'C' and (resid 14 through 156 )CC14 - 1561 - 143
1010chain 'C' and (resid 157 through 277 )CC157 - 277144 - 264
1111chain 'C' and (resid 278 through 330 )CC278 - 330265 - 317
1212chain 'C' and (resid 331 through 637 )CC331 - 637318 - 624
1313chain 'D' and (resid 27 through 82 )DD27 - 821 - 56
1414chain 'D' and (resid 83 through 196 )DD83 - 19657 - 170
1515chain 'D' and (resid 197 through 263 )DD197 - 263171 - 234
1616chain 'D' and (resid 264 through 328 )DD264 - 328235 - 299

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