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- PDB-7kic: PRMT5:MEP50 Complexed with 5,5-Bicyclic Inhibitor Compound 34 -

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Basic information

Entry
Database: PDB / ID: 7kic
TitlePRMT5:MEP50 Complexed with 5,5-Bicyclic Inhibitor Compound 34
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE / 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 / regulation of mitotic nuclear division / histone methyltransferase activity / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of gene expression via chromosomal CpG island methylation / E-box binding / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / regulation of ERK1 and ERK2 cascade / ribonucleoprotein complex binding / regulation of signal transduction by p53 class mediator / methyltransferase activity / liver regeneration / Regulation of TP53 Activity through Methylation / circadian regulation of gene expression / DNA-templated transcription termination / RMTs methylate histone arginines / protein polyubiquitination / transcription corepressor activity / p53 binding / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / chromatin remodeling / protein heterodimerization activity / positive regulation of cell population proliferation / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / 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 / 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 / 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
Chem-WFS / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 Å
AuthorsPalte, R.L.
CitationJournal: J.Med.Chem. / Year: 2021
Title: The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.
Authors: Quiroz, R.V. / Reutershan, M.H. / Schneider, S.E. / Sloman, D. / Lacey, B.M. / Swalm, B.M. / Yeung, C.S. / Gibeau, C. / Spellman, D.S. / Rankic, D.A. / Chen, D. / Witter, D. / Linn, D. / ...Authors: Quiroz, R.V. / Reutershan, M.H. / Schneider, S.E. / Sloman, D. / Lacey, B.M. / Swalm, B.M. / Yeung, C.S. / Gibeau, C. / Spellman, D.S. / Rankic, D.A. / Chen, D. / Witter, D. / Linn, D. / Munsell, E. / Feng, G. / Xu, H. / Hughes, J.M.E. / Lim, J. / Sauri, J. / Geddes, K. / Wan, M. / Mansueto, M.S. / Follmer, N.E. / Fier, P.S. / Siliphaivanh, P. / Daublain, P. / Palte, R.L. / Hayes, R.P. / Lee, S. / Kawamura, S. / Silverman, S. / Sanyal, S. / Henderson, T.J. / Ye, Y. / Gao, Y. / Nicholson, B. / Machacek, M.R.
History
DepositionOct 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 21, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)112,5119
Polymers111,6262
Non-polymers8857
Water5,891327
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5400 Å2
ΔGint6 kcal/mol
Surface area37460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.561, 138.836, 178.998
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-1011-

HOH

21A-1046-

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: Trichoplusia ni (cabbage looper)
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: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BQA1
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-WFS / (2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)oxy]-2-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexahydro-3aH-cyclopenta[b]furan-3,3a-diol


Mass: 512.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22BrN5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 327 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 57.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1 M sodium citrate pH 6.0, 0.2 M sodium acetate, 10-12% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.43→55 Å / Num. obs: 47006 / % possible obs: 96.5 % / Redundancy: 6.5 % / CC1/2: 1 / Net I/σ(I): 13.2
Reflection shellResolution: 2.44→2.53 Å / Redundancy: 5.5 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 3881 / CC1/2: 0.885 / % possible all: 80.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
HKL-3000data reduction
HKL-3000data scaling
HKL-3000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6UXX

6uxx


Resolution: 2.43→35.58 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.864 / SU R Cruickshank DPI: 0.377 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.383 / SU Rfree Blow DPI: 0.262 / SU Rfree Cruickshank DPI: 0.264
RfactorNum. reflection% reflectionSelection details
Rfree0.263 2359 5.02 %RANDOM
Rwork0.217 ---
obs0.22 46990 96.1 %-
Displacement parametersBiso max: 149.93 Å2 / Biso mean: 45.31 Å2 / Biso min: 5.76 Å2
Baniso -1Baniso -2Baniso -3
1--15.7363 Å20 Å20 Å2
2--4.167 Å20 Å2
3---11.5693 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 2.43→35.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7408 0 57 327 7792
Biso mean--34.35 38.09 -
Num. residues----936
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2601SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes189HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1142HARMONIC5
X-RAY DIFFRACTIONt_it7706HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion985SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8892SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7706HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10502HARMONIC30.91
X-RAY DIFFRACTIONt_omega_torsion3.72
X-RAY DIFFRACTIONt_other_torsion20.02
LS refinement shellResolution: 2.43→2.49 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3259 146 5.5 %
Rwork0.2846 2509 -
all0.287 2655 -
obs--73.87 %

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