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- PDB-9mgp: Crystal structure of PRMT5:MEP50 in complex with MTA and compound 46a -

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Basic information

Entry
Database: PDB / ID: 9mgp
TitleCrystal structure of PRMT5:MEP50 in complex with MTA and compound 46a
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / methyltransferase / inhibitor / 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 / MOLECULAR REPLACEMENT / Resolution: 2.67 Å
AuthorsWhittington, D.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design.
Authors: Cottrell, K.M. / Whittington, D.A. / Briggs, K.J. / Jahic, H. / Ali, J.A. / Amor, A.J. / Gotur, D. / Tonini, M.R. / Zhang, W. / Huang, A. / Maxwell, J.P.
History
DepositionDec 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release

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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)113,63726
Polymers111,6262
Non-polymers2,01124
Water2,036113
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)454,546104
Polymers446,5048
Non-polymers8,04296
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
Unit cell
Length a, b, c (Å)99.140, 137.690, 178.430
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22

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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 , 7 types, 137 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-A1BLI / [2-(cyclobutylamino)pyridin-4-yl][(3R,4R)-3-hydroxy-4-{6-[(1-methyl-1H-pyrazol-5-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl}piperidin-1-yl]methanone


Mass: 500.635 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H36N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
#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: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 113 / 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: 2.73 Å3/Da / Density % sol: 54.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 10% PEG 4000, 0.1 M sodium citrate (pH 6.0), 0.2 M magnesium chloride
PH range: 6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 31, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.67→45.1 Å / Num. obs: 35013 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.036 / Rrim(I) all: 0.093 / Χ2: 1.01 / Net I/σ(I): 14.9
Reflection shellResolution: 2.67→2.8 Å / % possible obs: 99.9 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.707 / Num. measured all: 29550 / Num. unique obs: 4592 / CC1/2: 0.934 / Rpim(I) all: 0.302 / Rrim(I) all: 0.77 / Χ2: 0.95 / Net I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.67→37.44 Å / SU ML: 0.4477 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 33.2614
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2708 1722 4.93 %RANDOM
Rwork0.22 33191 --
obs0.2226 34913 99.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 80.02 Å2
Refinement stepCycle: LAST / Resolution: 2.67→37.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7315 0 132 113 7560
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01357633
X-RAY DIFFRACTIONf_angle_d1.674910367
X-RAY DIFFRACTIONf_chiral_restr0.08981134
X-RAY DIFFRACTIONf_plane_restr0.00321333
X-RAY DIFFRACTIONf_dihedral_angle_d14.62842752
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.67-2.750.41891460.42212708X-RAY DIFFRACTION99.27
2.75-2.840.40511170.38892756X-RAY DIFFRACTION99.79
2.84-2.940.38361490.35182714X-RAY DIFFRACTION99.86
2.94-3.060.36341330.29942747X-RAY DIFFRACTION99.76
3.06-3.20.32141370.25722755X-RAY DIFFRACTION99.79
3.2-3.360.29441580.25762725X-RAY DIFFRACTION99.72
3.36-3.570.2911480.23622758X-RAY DIFFRACTION99.79
3.57-3.850.27761300.21322791X-RAY DIFFRACTION99.69
3.85-4.240.241620.19292749X-RAY DIFFRACTION99.93
4.24-4.850.21311380.16932776X-RAY DIFFRACTION99.93
4.85-6.10.25081540.18022809X-RAY DIFFRACTION99.66
6.11-37.440.23431500.17992903X-RAY DIFFRACTION98.9
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)
13.526619600250.6137779174130.5078549614092.98814335311-0.02496502432921.8781468576-0.130855076241-0.283507043345-0.2451190131250.263587148377-0.000123009938495-0.01661388600910.5659990862160.4167347150060.1309989306580.9650907809930.2438770391560.04646555817940.672615360283-0.03640295751790.29339557191722.9567439603-93.0320949562-17.8813576925
20.791741603813-0.418302176676-0.2886066904413.446742910251.575893648422.392914354140.08453448081140.1414516147480.0892679114582-0.4132380200460.0498587987793-0.363328649902-0.1799719241110.734799515458-0.1352928922750.8281297046560.06482216723610.09286038538830.8033606450350.05542799696240.40240938027926.9722278496-71.117125185-27.4278452003
31.675823636480.9391975395880.4577505022692.17561625240.7300862961471.56010243738-0.01496698528120.006519621885620.345274053545-0.110621101558-0.00425878201174-0.154229837831-1.027527514710.5450711344030.02051079457091.40337008538-0.3125207251530.06362524235870.6776190481650.04388445650950.42224182610121.2098062485-31.2590769211-9.94241836102
42.5519098550.6980819557620.08476618193591.576305051750.4551266744533.08045642207-0.02032020249960.0333253860029-0.117000876782-0.1447507058530.0176965287205-0.091041141509-0.5542838858260.0107458798724-0.03246744486630.8317594860190.01012492870090.03999128688910.482176474626-0.007174367344650.1915693876889.67856818899-51.4517932837-17.0114779805
52.135526714420.7076166142590.9857981397292.031972808910.05139726657021.832633576490.068729237770.30834332304-0.0275043814387-0.2620326688930.00512383464088-0.03444202817-0.5226873426370.205720120767-0.0622869482940.885928893693-0.03195427010490.02655364678620.486567818345-0.001873677872270.2823432798689.25127792503-50.6598765901-21.7933595123
64.516062538060.006786123760510.6169443496413.900867765543.768265325283.740898643830.2345660017120.100794717746-0.4461866913730.602044974829-0.207079745653-0.1214954152331.141877008980.660675183921-0.4425067642951.937920211320.7676811626420.1485568367311.053573281560.02456995247430.66953068335135.4150516769-115.052921405-28.0236575628
72.53227064997-0.988419479384-0.6911195461742.081196271351.081741598921.528217140750.1636892889510.1767923597690.192848575948-0.468724021577-0.176106864424-0.745093620580.3668849438591.07023251935-0.1708907716011.402726027320.6408433650730.09725108790161.28850361952-0.002085513204180.55060938346338.6627214587-103.776891148-39.5520492311
81.74045719245-0.989071265591-2.324410706732.998819940421.555690499665.149382595350.0846598053924-0.05890836866110.175012750355-0.48610182144-0.0808429564973-0.3907617852440.2918296348680.291272119833-0.1806962004171.759753617150.6039782359450.1104868823480.794299155311-0.2215537981610.11376107923823.7770523616-99.1214226482-47.9684379568
95.262403080330.82943832327-3.592842056873.793530334434.239183218678.757468582590.08272219424931.086986796610.0531489394697-0.930636460250.251139202580.256923497840.00850438081753-0.7814055177670.1964418474631.687841990160.290674810051-0.08316089883240.729149342538-0.05692104075680.52759699532813.2617757812-107.680533566-46.5101702086
103.07974983895-0.4750947847810.7608920155382.16854900691-0.3861490886561.66102918566-0.09794737123280.048071162794-0.8476765145240.4286686581530.1775957599690.184822926151.18919263631-0.001600596649970.1794590050712.036357934750.4853494598770.0200765726840.687054420687-0.1153296427860.62920533279119.1285441146-119.742593924-34.5236041098
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 149 )AA13 - 1491 - 137
22chain 'A' and (resid 150 through 330 )AA150 - 330138 - 318
33chain 'A' and (resid 331 through 487 )AA331 - 487319 - 475
44chain 'A' and (resid 488 through 533 )AA488 - 533476 - 518
55chain 'A' and (resid 534 through 637 )AA534 - 637519 - 622
66chain 'B' and (resid 28 through 89 )BB28 - 891 - 62
77chain 'B' and (resid 90 through 163 )BB90 - 16363 - 136
88chain 'B' and (resid 164 through 205 )BB164 - 205137 - 178
99chain 'B' and (resid 206 through 252 )BB206 - 252179 - 225
1010chain 'B' and (resid 253 through 328 )BB253 - 328226 - 301

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