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- PDB-9n3p: Crystal structure of PRMT5:MEP50 in complex with MTA and oxamide ... -

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Basic information

Entry
Database: PDB / ID: 9n3p
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and oxamide compound 30
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 / 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. / 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: 2.51 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)113,17914
Polymers111,6262
Non-polymers1,55312
Water6,269348
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)452,71556
Polymers446,5048
Non-polymers6,21148
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 area46670 Å2
ΔGint-396 kcal/mol
Surface area133980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.000, 138.300, 177.680
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 , 5 types, 360 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-A1BV3 / N-(6-amino-5-methylpyridin-3-yl)-2-[(2S,5R)-2-(4-fluorophenyl)-5-methyl-4-(2-methylpropanoyl)piperazin-1-yl]-2-oxoacetamide


Mass: 441.499 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H28FN5O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 348 / 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: 2.83 Å3/Da / Density % sol: 56.6 %
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: Diamond / Beamline: I03 / Wavelength: 0.97626 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Sep 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 2.51→54.63 Å / Num. obs: 43689 / % possible obs: 100 % / Redundancy: 13.9 % / Biso Wilson estimate: 53.99 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.131 / Net I/σ(I): 15.3
Reflection shellResolution: 2.51→2.6 Å / Redundancy: 13.3 % / Rmerge(I) obs: 1.404 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 4528 / CC1/2: 0.797 / Rpim(I) all: 0.415 / % possible all: 100

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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: 2.51→54.57 Å / SU ML: 0.3388 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.574
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2234 2192 5.02 %
Rwork0.1937 41484 -
obs0.1952 43676 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 65.84 Å2
Refinement stepCycle: LAST / Resolution: 2.51→54.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7353 0 99 348 7800
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00167669
X-RAY DIFFRACTIONf_angle_d0.484210452
X-RAY DIFFRACTIONf_chiral_restr0.04341142
X-RAY DIFFRACTIONf_plane_restr0.0041351
X-RAY DIFFRACTIONf_dihedral_angle_d12.50022765
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.560.31711490.30662544X-RAY DIFFRACTION99.96
2.56-2.620.30261280.28392561X-RAY DIFFRACTION100
2.62-2.690.29681390.26442575X-RAY DIFFRACTION99.96
2.69-2.760.29351230.25762556X-RAY DIFFRACTION100
2.76-2.840.26041300.24572547X-RAY DIFFRACTION99.96
2.84-2.940.29151300.24052610X-RAY DIFFRACTION100
2.94-3.040.3211350.25252565X-RAY DIFFRACTION99.96
3.04-3.160.24591410.22752566X-RAY DIFFRACTION100
3.16-3.310.2711210.21632599X-RAY DIFFRACTION100
3.31-3.480.23781480.19942566X-RAY DIFFRACTION100
3.48-3.70.22571300.19232603X-RAY DIFFRACTION100
3.7-3.980.19251510.17642590X-RAY DIFFRACTION100
3.98-4.380.2011500.15682579X-RAY DIFFRACTION99.93
4.38-5.020.17811340.15482623X-RAY DIFFRACTION100
5.02-6.320.18871410.1712636X-RAY DIFFRACTION100
6.32-54.570.20651420.17652764X-RAY DIFFRACTION99.69
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)
12.223124153920.06868134196540.3065650621422.52504381609-0.1239102360932.43795289356-0.0108461409056-0.0473208179051-0.1977109757150.0444014825908-0.0163255988523-0.08268173001320.3533991720290.4828177979260.03010522413290.4195782246310.1595375083880.01669179607110.476567880426-0.04243102416630.37519730282325.8567630128-95.2206402301-17.5331510965
25.189827292790.01235686250861.448000093284.8078342326-1.681003783481.013088581350.0656961638822-0.4999726342030.4081748952690.265132165421-0.1464116445950.3935909814490.0533474271465-0.1345269562180.1353202085320.4326498104580.0609836823030.05739659486410.458510068025-0.06866476430440.4214166887915.1329291587-86.3989557133-17.3427579434
31.95377814315-0.457447463360.589895219852.734066365820.4836766702972.434812130340.1594692165860.3205953024130.0406215231909-0.526781153678-0.119499203817-0.0787621665606-0.04955073917210.41122749054-0.01311447652270.4094206345560.06208837480490.05623614001150.473214898040.002503627156180.42218937198522.5854042937-78.0805630423-33.5215650778
44.243348611673.358057718310.3700026919635.06546117684-1.627184401184.797010996330.1191090251550.311550775290.325430923935-0.5196907504770.0191655456757-0.5201700889330.1193278752340.786781141758-0.2270401832070.3674995539570.04923802471230.08505727787780.745225960769-0.06024785114560.58540856316736.2870132303-75.4652879748-30.0524533544
54.52798729433-5.51615528558-4.851434534819.427348066797.381619263696.334849506740.321453948668-0.3363435297350.745730255029-0.51224148850.552785951409-1.34087601482-0.3720161783490.946695100081-0.8569865644660.433539436618-0.03510382508430.05382588776320.6698918059660.06689031990070.57421989776830.6935557593-60.4315926106-16.8950911394
61.379827218540.4035902890630.3209481579271.917698372650.6709319870662.216955462810.0380664540062-0.001101924101080.226182194224-0.009052842763270.0160045315846-0.21124006469-0.6961147072750.371373994196-0.03967618787360.476864159505-0.1192056478170.04359063016780.4009138087530.03101462547660.36555533327219.9437283247-36.9051291004-11.1468690712
71.563441365021.155605890091.146780444852.930258699480.837125227082.46656140457-0.0833570637050.207780580780.125158568749-0.2684695913580.107009546819-0.137181738714-0.6246765451460.26748918683-0.03888812186950.462491405126-0.03458183988050.06280149007940.4049343941090.05034809979990.32370706610914.5829831828-44.023947836-23.4982760704
83.00839119653-0.943433262588-0.8981054561863.288001254552.238026494984.55252282860.04485565073880.0849263121824-0.05389884204730.0698163011064-0.07535780093950.1376202115820.0374999454315-0.3823230130560.03594094477940.349982841731-0.00687155159159-0.0007649736652640.3687107691650.03447440713990.4106684105492.55383450488-53.7780556072-19.3363529162
91.16059249774-0.2302306792140.3926691062761.87624270077-0.1480420139192.545094567570.07260330920490.0693113409309-0.201011245514-0.169510889966-0.0713634830516-0.406170720170.7658013557010.7917307554180.0164275874160.7718350071570.4079980580620.05176339395720.792984051822-0.06224331333890.60469034042335.2361615228-106.733572216-36.7388645548
109.657941397961.68903468602-6.188175349344.515776328572.520829774069.200406456490.06478054115781.016672755810.0782918718617-1.26955840774-0.04394749945080.702654930556-0.0779396681474-0.5596639036290.0006615050589040.998867338650.264499974237-0.1470071091110.566822701381-0.05346147568230.64916848362215.019806665-109.105866506-43.9114362459
113.08674822341-0.5235817918491.127691573731.0058026428-1.274233908781.705206311940.1646930674590.331608361449-0.645000196761-0.0226649454441-0.03361441376210.08897796282181.057774625020.201051243085-0.1070738395171.198821263180.285535531522-0.04598719239320.571886535149-0.1226220634880.64903561069221.1955239599-121.346925288-33.9133931265
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 116 )AA13 - 1161 - 104
22chain 'A' and (resid 117 through 149 )AA117 - 149105 - 137
33chain 'A' and (resid 150 through 247 )AA150 - 247138 - 235
44chain 'A' and (resid 248 through 276 )AA248 - 276236 - 264
55chain 'A' and (resid 277 through 320 )AA277 - 320265 - 308
66chain 'A' and (resid 321 through 522 )AA321 - 522309 - 510
77chain 'A' and (resid 523 through 581 )AA523 - 581511 - 569
88chain 'A' and (resid 582 through 637 )AA582 - 637570 - 625
99chain 'B' and (resid 26 through 205 )BB26 - 2051 - 180
1010chain 'B' and (resid 206 through 263 )BB206 - 263181 - 238
1111chain 'B' and (resid 264 through 328 )BB264 - 328239 - 303

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