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- PDB-7s1q: PRMT5/MEP50 crystal structure with MTA and a phthalazinone inhibi... -

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Basic information

Entry
Database: PDB / ID: 7s1q
TitlePRMT5/MEP50 crystal structure with MTA and a phthalazinone inhibitor bound (Compound 9)
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-84W / 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: 2.78 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
DepositionSep 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 2, 2022Group: Database references / Structure summary / Category: audit_author / pdbx_database_related / Item: _audit_author.identifier_ORCID / _audit_author.name
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)112,1804
Polymers111,6262
Non-polymers5542
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-15 kcal/mol
Surface area37470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.342, 137.646, 178.660
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-807-

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-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S
#4: Chemical ChemComp-84W / [7-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl]methanaminium


Mass: 256.283 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14N5O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 56.78 %
Crystal growTemperature: 281 K / Method: vapor diffusion
Details: 100 mM Sodium Citrate pH 5, 18% PEG 4000, 150 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: Dec 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 28959 / % possible obs: 90 % / Redundancy: 2.8 % / Biso Wilson estimate: 56.78 Å2 / CC1/2: 0.99 / Net I/σ(I): 11.2
Reflection shellResolution: 2.75→2.8 Å / Mean I/σ(I) obs: 1.3 / Num. unique obs: 970 / CC1/2: 0.7 / % possible all: 60.7

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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: 2.78→46.69 Å / SU ML: 0.3683 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.2828
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2476 1506 5.21 %
Rwork0.2087 27413 -
obs0.2107 28919 88.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69 Å2
Refinement stepCycle: LAST / Resolution: 2.78→46.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7322 0 19 18 7359
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00187546
X-RAY DIFFRACTIONf_angle_d0.472310284
X-RAY DIFFRACTIONf_chiral_restr0.04291130
X-RAY DIFFRACTIONf_plane_restr0.0031329
X-RAY DIFFRACTIONf_dihedral_angle_d13.48732722
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.78-2.870.4339870.34831445X-RAY DIFFRACTION52.23
2.87-2.970.4061190.32761960X-RAY DIFFRACTION70.81
2.97-3.090.34781120.30232280X-RAY DIFFRACTION82.48
3.09-3.230.31751450.29112544X-RAY DIFFRACTION91.81
3.23-3.40.31971500.28642717X-RAY DIFFRACTION98.18
3.4-3.610.29111510.23322762X-RAY DIFFRACTION98.41
3.61-3.890.24451250.20372774X-RAY DIFFRACTION98.2
3.89-4.280.22911520.17682669X-RAY DIFFRACTION95.4
4.28-4.90.19331710.1632748X-RAY DIFFRACTION98.02
4.9-6.170.19561420.18122770X-RAY DIFFRACTION97.36
Refinement TLS params.Method: refined / Origin x: -28.7689039411 Å / Origin y: -76.0162842211 Å / Origin z: -24.7401232883 Å
111213212223313233
T0.33418478089 Å20.0820484436183 Å20.0564176401188 Å2-0.421714905959 Å2-0.0315809033687 Å2--0.33343253204 Å2
L0.0323453119307 °2-0.031427848692 °2-0.00446914542644 °2-0.19085031874 °2-0.0588437210741 °2--0.71639268871 °2
S0.0356455866985 Å °0.0681377621514 Å °0.0107343328828 Å °-0.10713017422 Å °-0.0795250458602 Å °0.0287156541008 Å °0.0679137071114 Å °0.319091358159 Å °-0.00554478712559 Å °
Refinement TLS groupSelection details: all

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