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- PDB-7s1p: PRMT5/MEP50 crystal structure with sinefungin bound -

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Basic information

Entry
Database: PDB / ID: 7s1p
TitlePRMT5/MEP50 crystal structure with sinefungin 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. / 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
SINEFUNGIN / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsGunn, R.J. / Thomas, N.C. / Lawson, J.D. / Ivetac, A. / Kulyk, S. / Smith, C.R. / 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
DepositionSep 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 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)112,0073
Polymers111,6262
Non-polymers3811
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4140 Å2
ΔGint-14 kcal/mol
Surface area37440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.755, 137.730, 178.249
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-827-

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 frugiperda (fall armyworm) / References: UniProt: Q9BQA1
#3: Chemical ChemComp-SFG / SINEFUNGIN / ADENOSYL-ORNITHINE


Mass: 381.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H23N7O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 2.66 Å3/Da / Density % sol: 53.7 %
Crystal growTemperature: 281 K / Method: vapor diffusion
Details: 100 mM Sodium Citrate pH 5.4, 15% PEG 3350, 4% Tacsimate 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: Oct 29, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.2→59.16 Å / Num. obs: 41740 / % possible obs: 69.5 % / Redundancy: 2.1 % / Biso Wilson estimate: 35.49 Å2 / CC1/2: 0.99 / Net I/σ(I): 9.5
Reflection shellResolution: 2.2→2.4 Å / Mean I/σ(I) obs: 0.9 / Num. unique obs: 444 / CC1/2: 0.53

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Processing

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

7s0u


Resolution: 2.21→44.46 Å / SU ML: 0.2699 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 31.9613
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2498 1582 5.14 %
Rwork0.2089 29189 -
obs0.2111 30771 51.12 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.62 Å2
Refinement stepCycle: LAST / Resolution: 2.21→44.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7185 0 27 130 7342
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00167398
X-RAY DIFFRACTIONf_angle_d0.467410073
X-RAY DIFFRACTIONf_chiral_restr0.04341117
X-RAY DIFFRACTIONf_plane_restr0.00361300
X-RAY DIFFRACTIONf_dihedral_angle_d10.7762664
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.21-2.280.3369150.3009416X-RAY DIFFRACTION7.97
2.28-2.360.3966290.3202549X-RAY DIFFRACTION10.67
2.36-2.450.3191320.3226734X-RAY DIFFRACTION14.2
2.45-2.560.3468520.3188842X-RAY DIFFRACTION16.56
2.56-2.70.3102680.29321361X-RAY DIFFRACTION26.33
2.7-2.870.33421130.28062010X-RAY DIFFRACTION38.98
2.87-3.090.30071820.26983264X-RAY DIFFRACTION63.57
3.09-3.40.29742660.23724854X-RAY DIFFRACTION93.23
3.4-3.890.24142580.20014931X-RAY DIFFRACTION94.62
3.89-4.90.20362810.16875183X-RAY DIFFRACTION98.65
4.9-44.460.23562860.19415045X-RAY DIFFRACTION93.2
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)
10.756659698368-0.02848929890930.2141994389780.680355591144-0.003062761079620.706144039469-0.0602789709015-0.00885325364866-0.03072133571550.05421576897810.0718180030364-0.05970753466510.2112375094280.253147046583-0.01174900726410.1362389368950.0959471184240.02875176826380.241595472409-0.05467822798520.192226226736-25.4436868675-93.0903504768-17.9138786969
20.706882935827-0.153890396023-0.1735337339380.630151340594-0.02636020223330.4382448210250.03809517366680.08921310556730.217862966186-0.2337912467590.00072574444398-0.161202369334-0.1468195000120.296702895824-0.03439861266180.1231854714430.006093937496670.07322017838960.277779065561-0.008832391775630.244914200217-21.6173336564-74.7590817767-30.5863209065
30.587716317468-0.2363756658250.2618502864220.1751323502930.04542481094090.568664326221-0.009987566075450.05533196155170.07641190174970.02862064942290.00250185743167-0.135526873141-0.3967448658810.30907550962-0.009065424143770.30139016028-0.1894983520730.01948966377460.19756454440.01845008699220.205487692621-28.8164127827-36.9356544384-10.3906370521
41.078548849830.3889752832430.03482817890530.997435224034-0.09649525114981.180154145030.04792258601190.295006213630.017281701854-0.0749165710796-0.04100617603010.0580962798774-0.2838900596280.0619698891662-0.0006413567245060.1191833201390.0356783974303-0.01047460882520.174945335464-0.0121524200860.0906998016034-39.6456372892-48.4997869949-21.3931015547
50.805869506474-0.510805492991-0.5735983097751.269687636030.9516798295620.887340990322-0.0190508699264-0.0170565366827-0.06506136509650.04705384402650.0694552032355-0.062786680880.08973224877270.08318371560960.0111290153210.711650594880.2836694289740.151153911510.530153033599-0.1337770884150.456314657055-15.183387447-117.013548329-30.7326854054
60.149726582191-0.0799062515569-0.2164482532790.1023646976660.2474959412680.60273931139-0.0776400977174-0.000792376369592-0.2799096932540.03619491330590.057832851501-0.1139631706440.3285692286910.149769863728-0.00404902419220.7023474017780.3611415529930.02943043060680.544280535708-0.06413537135260.455187942387-11.4200780992-114.252672734-26.6444661636
70.474668666376-0.320853987639-0.08567053553250.4361261735660.1799653721620.110220195136-0.06058718380170.129857881892-0.202624480542-0.06678297017080.1524506406-0.2595097421630.1335207155870.199176981381-0.02386073014920.6219048197460.3299942207350.1469477729510.594839404911-0.06221560068080.408012630374-7.90843116105-108.131240575-36.2516460349
80.393635822304-0.103520659733-0.2868442879470.06294766328030.1781968503170.4964386381550.0867405216810.124858148267-0.0589850621469-0.1512987377240.0446648155686-0.2908219723210.1897575122750.3156501724130.0008509131613450.4614024086980.2658498314410.1247681559480.491451455357-0.09897351176040.34162772655-12.4416491613-101.416269075-40.7192163518
90.257230741477-0.1446519833110.007411087586810.6682230727440.02334460485790.5292484970880.06758387336640.162102696484-0.0461649292014-0.2279420509080.0620920663989-0.157606957430.1638423150790.06671270230990.1363295547910.5467454048810.1753124101290.05696476575190.350717392-0.1416297479240.238745101089-26.7548327313-102.981695582-49.1536614091
100.537649791158-0.0576429346167-0.1692944571730.6462479436480.3409437018930.76999682021-0.01402743899580.211945885948-0.178723383902-0.247653879484-0.07154259239760.04766415663050.1921098496530.02389747269270.01651363059480.7520995546010.0598596848065-0.01700380573150.300352795124-0.1582818469350.344292113152-33.6847917484-113.333018636-41.5720585398
110.3514827119460.08905867889480.4882745736461.143506882710.4993382373081.36427710237-0.02466093553140.0434579941012-0.231834352723-0.09503796772840.06975337204950.1632487595460.236371175276-0.09279702223450.02004209545270.8335395526150.0850609573661-0.04572584027940.291125719816-0.09838701939330.355319347578-31.8717836572-118.853717977-32.8574215537
120.35182826853-0.20298546643-0.2317387615870.4233185613350.2648555495760.2094135492960.01482536711110.0814590634898-0.176162525271-0.01746425850750.0234815070538-0.0007403591686930.1391438516260.03408626226960.02408817720940.8147175030270.1758995563160.02897804759170.314806700404-0.1026118377770.368470449965-23.2338941652-124.087602464-32.2095489197
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 311 )AA150 - 311138 - 290
33chain 'A' and (resid 312 through 522 )AA312 - 522291 - 501
44chain 'A' and (resid 523 through 637 )AA523 - 637502 - 616
55chain 'B' and (resid 27 through 47 )BC27 - 471 - 21
66chain 'B' and (resid 48 through 89 )BC48 - 8922 - 62
77chain 'B' and (resid 90 through 108 )BC90 - 10863 - 81
88chain 'B' and (resid 109 through 175 )BC109 - 17582 - 148
99chain 'B' and (resid 176 through 226 )BC176 - 226149 - 195
1010chain 'B' and (resid 227 through 275 )BC227 - 275196 - 239
1111chain 'B' and (resid 276 through 305 )BC276 - 305240 - 269
1212chain 'B' and (resid 306 through 328 )BC306 - 328270 - 292

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