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- PDB-7ser: PRMT5/MEP50 with compound 30 bound -

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Basic information

Entry
Database: PDB / ID: 7ser
TitlePRMT5/MEP50 with compound 30 bound
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/INHIBITOR / PRMT5 / MTAP / MTA / methyl transferase / collateral lethality / synthetic lethality / fragment-based lead discovery / 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. / Divalent-metal-dependent TIM barrel enzymes / 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 / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-97L / 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: 2.14 Å
AuthorsGunn, R.J. / Thomas, N.C. / Lawson, J.D. / Ivetac, A. / Smith, C.R. / Kulyk, S. / Marx, M.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP -Deleted Cancers.
Authors: Smith, C.R. / Aranda, R. / Bobinski, T.P. / Briere, D.M. / Burns, A.C. / Christensen, J.G. / Clarine, J. / Engstrom, L.D. / Gunn, R.J. / Ivetac, A. / Jean-Baptiste, R. / Ketcham, J.M. / ...Authors: Smith, C.R. / Aranda, R. / Bobinski, T.P. / Briere, D.M. / Burns, A.C. / Christensen, J.G. / Clarine, J. / Engstrom, L.D. / Gunn, R.J. / Ivetac, A. / Jean-Baptiste, R. / Ketcham, J.M. / Kobayashi, M. / Kuehler, J. / Kulyk, S. / Lawson, J.D. / Moya, K. / Olson, P. / Rahbaek, L. / Thomas, N.C. / Wang, X. / Waters, L.M. / Marx, M.A.
History
DepositionOct 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Category: pdbx_database_related
Revision 1.2Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)112,3364
Polymers111,6262
Non-polymers7102
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4770 Å2
ΔGint-13 kcal/mol
Surface area38210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.891, 138.305, 179.191
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
Components on special symmetry positions
IDModelComponents
11A-927-

HOH

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Components

#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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PRMT5, HRMT1L5, IBP72, JBP1, SKB1 / Production host: Spodoptera frugiperda (fall armyworm)
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: Spodoptera (butterflies/moths) / References: UniProt: Q9BQA1
#3: Chemical ChemComp-97L / (2M)-2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}-1-benzothiophene-3-carbonitrile


Mass: 412.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H16N6OS / Feature type: SUBJECT OF INVESTIGATION
#4: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.88 Å3/Da / Density % sol: 57.34 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 100 mM Sodium Citrate pH 5.4, 12% PEG 3350, 4% Tascimate pH 5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 25, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.14→50 Å / Num. obs: 61203 / % possible obs: 85.9 % / Redundancy: 2.8 % / Biso Wilson estimate: 37.99 Å2 / CC1/2: 0.99 / Net I/σ(I): 16.1
Reflection shellResolution: 2.14→2.18 Å / Num. unique obs: 1684 / CC1/2: 0.91

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7S0U

7s0u


Resolution: 2.14→46.93 Å / SU ML: 0.2703 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 32.8784
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2526 3027 4.95 %
Rwork0.2056 58176 -
obs0.2079 61203 85.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 55.14 Å2
Refinement stepCycle: LAST / Resolution: 2.14→46.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7361 0 50 231 7642
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00747621
X-RAY DIFFRACTIONf_angle_d0.82810390
X-RAY DIFFRACTIONf_chiral_restr0.05321140
X-RAY DIFFRACTIONf_plane_restr0.00781342
X-RAY DIFFRACTIONf_dihedral_angle_d12.74932768
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.14-2.170.3308780.2731455X-RAY DIFFRACTION48.28
2.17-2.210.3456900.27051514X-RAY DIFFRACTION50.2
2.21-2.250.32851000.26981718X-RAY DIFFRACTION56.69
2.25-2.290.3202790.28431837X-RAY DIFFRACTION59.97
2.29-2.330.3191030.27742028X-RAY DIFFRACTION66.74
2.33-2.380.40521090.28882277X-RAY DIFFRACTION73.76
2.38-2.430.341210.30212531X-RAY DIFFRACTION82.49
2.43-2.490.36761430.28052707X-RAY DIFFRACTION88.59
2.49-2.550.31321450.26932860X-RAY DIFFRACTION93.41
2.55-2.620.3181660.26752956X-RAY DIFFRACTION97.56
2.62-2.70.28561520.25323030X-RAY DIFFRACTION98.79
2.7-2.780.30231560.24853030X-RAY DIFFRACTION99.01
2.78-2.880.24221650.24993052X-RAY DIFFRACTION98.95
2.88-30.29411570.25183011X-RAY DIFFRACTION98.75
3-3.130.28821590.22713043X-RAY DIFFRACTION98.67
3.13-3.30.30481480.20722934X-RAY DIFFRACTION95.6
3.3-3.510.24341660.18923021X-RAY DIFFRACTION97.94
3.51-3.780.23511670.18133079X-RAY DIFFRACTION98.96
3.78-4.160.19791810.15743040X-RAY DIFFRACTION98.62
4.16-4.760.17231520.14063012X-RAY DIFFRACTION97.03
4.76-5.990.20631660.16943021X-RAY DIFFRACTION95.97
5.99-46.930.2741240.21463020X-RAY DIFFRACTION91.34
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)
11.63377521366-0.2789159699080.3603914898851.3194279793-0.05176453282191.82397548053-0.0436118307929-0.104095536136-0.08350512667390.1272571244580.033915138021-0.008303828350050.6021381970360.4787171298260.00949432248740.3943261745080.192993529070.0326743341140.4034947226-0.04187529595260.292436106784-28.7301101338-93.1989843595-17.7321062065
22.04715412358-0.03008228358890.06503656373291.942467906410.3930351900611.494194604640.1389442461050.3305357826320.192351966431-0.602552984081-0.0895820367798-0.17152494493-0.1353044085150.428598953279-0.06490390868950.3920884314880.1045906069040.1188717901360.456750306888-0.007610066150290.361819267658-26.1124361116-77.3612017523-32.957902712
30.0503218674883-0.182311944283-0.2548056831240.8184279866220.5005921217910.7748005446360.09910005916320.07768846863620.0274305780233-0.410439919694-0.00470496016586-0.384062486115-0.2639826480430.690642976416-0.2194112098770.415480712413-0.06009537043250.09733068630030.630141808865-0.05413674831530.470729161967-21.4678656993-57.4244635696-14.7159601237
41.336024056930.4837785614910.4448348297881.331000371840.4884110024441.56065066537-0.06110593732280.09001322507310.130627234899-0.1665728706780.0492016668518-0.157449689598-0.7037470844720.265201550864-0.0232909154720.451623793967-0.1221936787250.03072726293830.2808988244360.02328929343830.285011247031-36.6100494765-41.0682010824-15.2258736289
51.97850657136-1.11486340827-1.237354093772.702067790041.882077617951.45903643931-0.079883483066-0.192056061177-0.2114674126250.324100420440.324907313229-0.4791161271020.4631636240340.554915887682-0.189251047611.132816031560.6941360964990.2369883326150.697415042802-0.06227991381990.589141201949-15.0917303402-117.155096009-28.1544118992
60.373468749696-0.1548759546660.01652308205651.200039383040.4623804765610.251987326246-0.02187840557290.0516258167536-0.141591086721-0.3546279535590.0506046584591-0.3069945902490.7494509049640.5863354123620.02641611146390.9081398140670.5068750132180.1294147276640.761114163151-0.06364540930790.502105281291-16.3754805754-105.986883909-36.9916822113
71.413044249590.990133883571-0.8375378067861.14533330832-0.6216551797350.494767658419-0.01247574006440.564849285504-0.204674987135-0.4800080975360.00665806255598-0.1467055219190.671640942808-0.2088220430440.0101242424450.9489442952950.180600260184-0.03040132583020.511200744801-0.1108420452230.44579121617-33.8808698089-105.745041724-47.4408204155
82.33473825326-0.387627105699-0.271993851511.617543864730.3805286613760.113698064978-0.1433335210160.297306413863-0.55759948863-0.1942480714940.04183559733970.2608019121030.8622045553240.262016263370.1375834261481.329278046480.2602401704940.03717809736530.515399470736-0.1687240090420.572571622289-32.7053510817-119.366070954-35.7432961536
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 276 )AA150 - 276138 - 264
33chain 'A' and (resid 277 through 330 )AA277 - 330265 - 318
44chain 'A' and (resid 331 through 637 )AA331 - 637319 - 625
55chain 'B' and (resid 19 through 47 )BD19 - 471 - 29
66chain 'B' and (resid 48 through 196 )BD48 - 19630 - 178
77chain 'B' and (resid 197 through 241 )BD197 - 241179 - 220
88chain 'B' and (resid 242 through 329 )BD242 - 329221 - 305

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