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- PDB-7mxc: PRMT5:MEP50 complexed with adenosine -

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Basic information

Entry
Database: PDB / ID: 7mxc
TitlePRMT5:MEP50 complexed with adenosine
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/Transcription / arginine / methyl / transferase / TRANSFERASE-Transcription 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 / spliceosomal snRNP assembly / regulation of ERK1 and ERK2 cascade / ubiquitin-like ligase-substrate adaptor activity / ribonucleoprotein complex binding / liver regeneration / regulation of signal transduction by p53 class mediator / methyltransferase activity / Regulation of TP53 Activity through Methylation / circadian regulation of gene expression / DNA-templated transcription termination / 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 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 / Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 ...: / 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 / Hnrnp arginine n-methyltransferase1 / Hnrnp arginine n-methyltransferase1 / Protein arginine N-methyltransferase / SAM-dependent methyltransferase PRMT-type domain profile. / Divalent-metal-dependent TIM barrel enzymes / Vaccinia Virus protein VP39 / Distorted Sandwich / 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 / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
ADENOSINE / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.41 Å
AuthorsMcTigue, M. / Deng, Y.L. / Liu, W. / Brooun, A.
CitationJournal: Mol.Cancer Ther. / Year: 2022
Title: SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.
Authors: Jensen-Pergakes, K. / Tatlock, J. / Maegley, K.A. / McAlpine, I.J. / McTigue, M. / Xie, T. / Dillon, C.P. / Wang, Y. / Yamazaki, S. / Spiegel, N. / Shi, M. / Nemeth, A. / Miller, N. / ...Authors: Jensen-Pergakes, K. / Tatlock, J. / Maegley, K.A. / McAlpine, I.J. / McTigue, M. / Xie, T. / Dillon, C.P. / Wang, Y. / Yamazaki, S. / Spiegel, N. / Shi, M. / Nemeth, A. / Miller, N. / Hendrickson, E. / Lam, H. / Sherrill, J. / Chung, C.Y. / McMillan, E.A. / Bryant, S.K. / Palde, P. / Braganza, J. / Brooun, A. / Deng, Y.L. / Goshtasbi, V. / Kephart, S.E. / Kumpf, R.A. / Liu, W. / Patman, R.L. / Rui, E. / Scales, S. / Tran-Dube, M. / Wang, F. / Wythes, M. / Paul, T.A.
History
DepositionMay 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 17, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 19, 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.year / _citation_author.name
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)112,5543
Polymers112,2872
Non-polymers2671
Water3,855214
1
A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules

A: Protein arginine N-methyltransferase 5
B: Methylosome protein 50
hetero molecules


Theoretical massNumber of molelcules
Total (without water)450,21612
Polymers449,1478
Non-polymers1,0694
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_445-x-1,-y-1,z1
crystal symmetry operation3_455-x-1,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area33150 Å2
ΔGint-88 kcal/mol
Surface area134690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.923, 137.956, 177.942
Angle α, β, γ (deg.)90, 90, 90
Int Tables number23
Space group name H-MI222

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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: 72766.664 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: 39520.082 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-ADN / ADENOSINE


Mass: 267.241 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13N5O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 2.73 Å3/Da / Density % sol: 54.96 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop
Details: Crystallization of full-length human PRMT5/MEP50 complexed with cofactor site inhibitors was performed at 13 degrees Celsius by hanging-drop vapor-diffusion methods. 2.5 ul of a solution of ...Details: Crystallization of full-length human PRMT5/MEP50 complexed with cofactor site inhibitors was performed at 13 degrees Celsius by hanging-drop vapor-diffusion methods. 2.5 ul of a solution of 5:1 molar ratio of inhibitor compound to PRMT5/MEP50 complex (13 mg/mL) was mixed with 2.5 ul of reservoir solution containing 13-15% (w/v) PEG3350, 0.1M MES, pH 6.5-7.5, 0.25M NaCl, and 20% (v/v) ethylene glycol

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.41→109.03 Å / Num. obs: 47892 / % possible obs: 99.7 % / Redundancy: 6 % / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.044 / Net I/σ(I): 11.9
Reflection shellResolution: 2.41→2.54 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.706 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 6892 / Rpim(I) all: 0.323 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
BUSTER2.11.7phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3GQB

3gqb


Resolution: 2.41→109.03 Å / Cor.coef. Fo:Fc: 0.847 / Cor.coef. Fo:Fc free: 0.805 / SU R Cruickshank DPI: 0.39 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.386 / SU Rfree Blow DPI: 0.285 / SU Rfree Cruickshank DPI: 0.289
RfactorNum. reflection% reflectionSelection details
Rfree0.3031 2392 -RANDOM
Rwork0.2481 ---
obs0.2509 47768 99.3 %-
Displacement parametersBiso mean: 65.08 Å2
Baniso -1Baniso -2Baniso -3
1--37.4154 Å20 Å20 Å2
2--7.3344 Å20 Å2
3---30.081 Å2
Refine analyzeLuzzati coordinate error obs: 0.46 Å
Refinement stepCycle: LAST / Resolution: 2.41→109.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7286 0 19 214 7519
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0087514HARMONIC2
X-RAY DIFFRACTIONt_angle_deg110238HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2535SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1284HARMONIC5
X-RAY DIFFRACTIONt_it7514HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion964SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6010SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion19.9
LS refinement shellResolution: 2.41→2.42 Å
RfactorNum. reflection% reflection
Rfree0.4624 48 -
Rwork0.3186 --
obs--96.82 %

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