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- PDB-7s1s: PRMT5/MEP50 crystal structure with MTA and MRTX-1719 bound -

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Basic information

Entry
Database: PDB / ID: 7s1s
TitlePRMT5/MEP50 crystal structure with MTA and MRTX-1719 bound
Components
  • Methylosome protein 50WD repeat-containing protein 77
  • 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 / histone H4R3 methyltransferase activity / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development ...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 / histone H4R3 methyltransferase activity / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development / epithelial cell proliferation involved in prostate gland development / histone arginine N-methyltransferase activity / methylosome / protein-arginine N-methyltransferase activity / methyl-CpG binding / positive regulation of mRNA splicing, via spliceosome / : / endothelial cell activation / histone H3 methyltransferase activity / Cul4B-RING E3 ubiquitin ligase complex / regulation of mitotic nuclear division / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / histone methyltransferase activity / E-box binding / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / nuclear receptor coactivator activity / regulation of signal transduction by p53 class mediator / methyltransferase activity / liver regeneration / DNA-templated transcription termination / circadian regulation of gene expression / Regulation of TP53 Activity through Methylation / RMTs methylate histone arginines / protein polyubiquitination / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / chromatin remodeling / protein heterodimerization activity / positive regulation of cell population proliferation / chromatin / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Protein arginine N-methyltransferase PRMT5 / PRMT5 arginine-N-methyltransferase / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / WD40 repeat, conserved site ...Protein arginine N-methyltransferase PRMT5 / PRMT5 arginine-N-methyltransferase / PRMT5, TIM barrel domain / PRMT5, oligomerisation domain / PRMT5 arginine-N-methyltransferase / PRMT5 TIM barrel domain / PRMT5 oligomerisation domain / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Chem-85K / 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: 2.62 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 1.0Jan 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)112,3894
Polymers111,6262
Non-polymers7632
Water1,15364
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4810 Å2
ΔGint-15 kcal/mol
Surface area37490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.140, 138.095, 178.800
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

#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 / WD repeat-containing protein 77 / 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-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE / 5′-Methylthioadenosine


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S
#4: Chemical ChemComp-85K / (7-{(5M)-5-[3-chloro-6-cyano-5-(cyclopropyloxy)-2-fluorophenyl]-1-methyl-1H-pyrazol-4-yl}-4-oxo-3,4-dihydrophthalazin-1-yl)methanaminium


Mass: 465.887 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H19ClFN6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 2.85 Å3/Da / Density % sol: 56.87 %
Crystal growTemperature: 281 K / Method: vapor diffusion
Details: 100 mM Sodium Citrate pH 5.4, 11% PEG 4000, 50 mM Sodium Acetate

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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: Mar 19, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 34297 / % possible obs: 88.2 % / Redundancy: 2.7 % / Biso Wilson estimate: 50.67 Å2 / CC1/2: 0.99 / Net I/σ(I): 11.3
Reflection shellResolution: 2.6→2.64 Å / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1083 / CC1/2: 0.6

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7S0U

7s0u


Resolution: 2.62→46.64 Å / SU ML: 0.407 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.7646
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2332 1772 5.17 %
Rwork0.2086 32510 -
obs0.2099 34282 88.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 63.82 Å2
Refinement stepCycle: LAST / Resolution: 2.62→46.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7356 0 33 64 7453
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00227598
X-RAY DIFFRACTIONf_angle_d0.498410361
X-RAY DIFFRACTIONf_chiral_restr0.04331138
X-RAY DIFFRACTIONf_plane_restr0.00421337
X-RAY DIFFRACTIONf_dihedral_angle_d13.64212740
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.62-2.690.4267890.35641542X-RAY DIFFRACTION55.06
2.69-2.760.32971030.33411942X-RAY DIFFRACTION69.2
2.77-2.850.35481330.31212077X-RAY DIFFRACTION75.14
2.85-2.960.36511470.30752283X-RAY DIFFRACTION81.33
2.96-3.070.34541190.31232567X-RAY DIFFRACTION90.74
3.07-3.210.31211490.28222712X-RAY DIFFRACTION96.88
3.21-3.380.33431260.25852797X-RAY DIFFRACTION98.15
3.38-3.60.26531550.22992740X-RAY DIFFRACTION97.05
3.6-3.870.24811350.21162725X-RAY DIFFRACTION95.84
3.87-4.260.1981530.17042755X-RAY DIFFRACTION96.48
4.26-4.880.15891650.14682783X-RAY DIFFRACTION98.43
4.88-6.140.17011590.16852815X-RAY DIFFRACTION97.8
6.15-46.640.18861390.16462772X-RAY DIFFRACTION91.63
Refinement TLS params.Method: refined / Origin x: -28.6810161599 Å / Origin y: -76.2635470691 Å / Origin z: -24.6908676139 Å
111213212223313233
T0.244898718591 Å20.0541869470868 Å20.0482709741131 Å2-0.398367668882 Å2-0.0385705115728 Å2--0.338498020853 Å2
L0.0857401969726 °2-0.0648761492623 °20.0135833548569 °2-0.172208836496 °2-0.101450424487 °2--0.861684040486 °2
S0.0347069283241 Å °0.0523059022868 Å °-0.00220903199447 Å °-0.174977648678 Å °-0.0440436890944 Å °0.019060930956 Å °0.0661291211882 Å °0.277299712709 Å °-0.000589034129452 Å °
Refinement TLS groupSelection details: all

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