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- PDB-8ctb: Human PRMT5:MEP50 structure with Fragment 3 and MTA Bound -

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Basic information

Entry
Database: PDB / ID: 8ctb
TitleHuman PRMT5:MEP50 structure with Fragment 3 and MTA Bound
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / MTAP / methyl transferase / fragment-based lead discovery / FBDD
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 / peptidyl-arginine methylation / protein-arginine omega-N symmetric methyltransferase activity / 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 arginine N-methyltransferase activity ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / oocyte axis specification / type II protein arginine methyltransferase / peptidyl-arginine methylation / protein-arginine omega-N symmetric methyltransferase activity / 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 arginine N-methyltransferase activity / epithelial cell proliferation involved in prostate gland development / histone H3R17 methyltransferase activity / histone H3R2 methyltransferase activity / histone H3R8 methyltransferase activity / histone H3R26 methyltransferase activity / histone H4R3 methyltransferase activity / histone H3K37 methyltransferase activity / histone H4K12 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / histone H2A Q104 methyltransferase activity / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / regulation of ERK1 and ERK2 cascade / spliceosomal snRNP assembly / ribonucleoprotein complex binding / : / 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 / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / 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 / cytosol / cytoplasm
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 / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / WD40/YVTN repeat-like-containing domain superfamily / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
5'-DEOXY-5'-METHYLTHIOADENOSINE / 7-chloro-1-methyl-1H-benzimidazol-2-amine / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsGunn, R.J. / Lawson, J.D. / Smith, C.R.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Rsc Med Chem / Year: 2022
Title: Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.
Authors: Smith, C.R. / Kulyk, S. / Ahmad, M.U.D. / Arkhipova, V. / Christensen, J.G. / Gunn, R.J. / Ivetac, A. / Ketcham, J.M. / Kuehler, J. / Lawson, J.D. / Thomas, N.C. / Wang, X. / Marx, M.A.
History
DepositionMay 13, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 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)112,1054
Polymers111,6262
Non-polymers4792
Water57632
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4890 Å2
ΔGint-15 kcal/mol
Surface area38070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.983, 137.232, 178.304
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 / Fragment: FULL LENGTH
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-PWX / 7-chloro-1-methyl-1H-benzimidazol-2-amine


Mass: 181.622 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H8ClN3 / 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.: 32 / 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: 2.68 Å3/Da / Density % sol: 54.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 10% PEG 8000, 100 mM Sodium Citrate 5.4, 100 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: Jun 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.61→44.7 Å / Num. obs: 28091 / % possible obs: 76.1 % / Redundancy: 2.7 % / Biso Wilson estimate: 44.62 Å2 / CC1/2: 0.99 / Net I/σ(I): 9.4
Reflection shellResolution: 2.61→2.64 Å / Rmerge(I) obs: 0.6 / Num. unique obs: 427

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7UY1

7uy1


Resolution: 2.61→44.67 Å / SU ML: 0.4265 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 36.7555
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2885 1407 5.01 %
Rwork0.2465 26684 -
obs0.2486 28091 76.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 54.43 Å2
Refinement stepCycle: LAST / Resolution: 2.61→44.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7319 0 32 32 7383
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00187556
X-RAY DIFFRACTIONf_angle_d0.442210296
X-RAY DIFFRACTIONf_chiral_restr0.04221132
X-RAY DIFFRACTIONf_plane_restr0.00331330
X-RAY DIFFRACTIONf_dihedral_angle_d11.21962730
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.61-2.70.3607430.3113919X-RAY DIFFRACTION26.6
2.7-2.810.3614900.33041452X-RAY DIFFRACTION42.44
2.81-2.940.35031190.31511928X-RAY DIFFRACTION56.02
2.94-3.090.36531170.33452388X-RAY DIFFRACTION68.78
3.09-3.290.35061600.32612952X-RAY DIFFRACTION84.73
3.29-3.540.35331640.30123384X-RAY DIFFRACTION96.94
3.54-3.90.31471590.26013406X-RAY DIFFRACTION96.56
3.9-4.460.26491810.21863395X-RAY DIFFRACTION96.73
4.46-5.620.23861840.20413455X-RAY DIFFRACTION97.17
5.62-44.670.24891900.20323405X-RAY DIFFRACTION92.87

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