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- PDB-6ckc: Structure of PRMT5:MEP50 in complex with LLY-283, a potent and se... -

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Basic information

Entry
Database: PDB / ID: 6ckc
TitleStructure of PRMT5:MEP50 in complex with LLY-283, a potent and selective inhibitor of PRMT5, with antitumor activity
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE / 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 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 / 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 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 H3K37 methyltransferase activity / histone H4K12 methyltransferase activity / histone H4R3 methyltransferase activity / histone H3K56 methyltransferase activity / protein-arginine N-methyltransferase activity / methylosome / positive regulation of mRNA splicing, via spliceosome / methyl-CpG binding / histone H2AQ104 methyltransferase activity / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase complex / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of gene expression via chromosomal CpG island methylation / histone methyltransferase activity / E-box binding / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / 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 / 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 / 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / Vaccinia Virus protein VP39 / 7 Propeller / Methylamine Dehydrogenase; Chain H / Distorted Sandwich / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / 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
Chem-F5J / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.8 Å
AuthorsAntonysamy, S.
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity.
Authors: Bonday, Z.Q. / Cortez, G.S. / Grogan, M.J. / Antonysamy, S. / Weichert, K. / Bocchinfuso, W.P. / Li, F. / Kennedy, S. / Li, B. / Mader, M.M. / Arrowsmith, C.H. / Brown, P.J. / Eram, M.S. / ...Authors: Bonday, Z.Q. / Cortez, G.S. / Grogan, M.J. / Antonysamy, S. / Weichert, K. / Bocchinfuso, W.P. / Li, F. / Kennedy, S. / Li, B. / Mader, M.M. / Arrowsmith, C.H. / Brown, P.J. / Eram, M.S. / Szewczyk, M.M. / Barsyte-Lovejoy, D. / Vedadi, M. / Guccione, E. / Campbell, R.M.
History
DepositionFeb 27, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 8, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)111,5073
Polymers111,1652
Non-polymers3421
Water1,22568
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)446,02812
Polymers444,6588
Non-polymers1,3694
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 area30210 Å2
ΔGint-88 kcal/mol
Surface area134090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)102.785, 139.077, 178.961
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 74281.250 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: 36883.332 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-F5J / 7-[(5R)-5-C-phenyl-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 342.349 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18N4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O

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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: 57.24 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop
Details: 16% PEG 3350, 200mM Magnesium Chloride, 100mM Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9798 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Sep 20, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9798 Å / Relative weight: 1
ReflectionResolution: 2.8→61 Å / Num. obs: 31922 / % possible obs: 99.9 % / Redundancy: 7.4 % / Biso Wilson estimate: 63.69 Å2 / Net I/σ(I): 13.3
Reflection shellResolution: 2.8→2.95 Å

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Processing

Software
NameVersionClassification
SCALAdata scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementResolution: 2.8→60.72 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.898 / SU R Cruickshank DPI: 0.853 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.778 / SU Rfree Blow DPI: 0.28 / SU Rfree Cruickshank DPI: 0.287
RfactorNum. reflection% reflectionSelection details
Rfree0.214 1644 5.15 %RANDOM
Rwork0.178 ---
obs0.18 31922 99.9 %-
Displacement parametersBiso max: 172.43 Å2 / Biso mean: 75.37 Å2 / Biso min: 22.82 Å2
Baniso -1Baniso -2Baniso -3
1--31.5434 Å20 Å20 Å2
2--7.0965 Å20 Å2
3---24.4469 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: final / Resolution: 2.8→60.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7255 0 25 68 7348
Biso mean--43.7 52.39 -
Num. residues----928
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2474SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes179HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1089HARMONIC5
X-RAY DIFFRACTIONt_it7485HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion971SEMIHARMONIC5
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_contact8146SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7485HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10215HARMONIC21.15
X-RAY DIFFRACTIONt_omega_torsion3.4
X-RAY DIFFRACTIONt_other_torsion17.67
LS refinement shellResolution: 2.8→2.89 Å / Rfactor Rfree error: 0 / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2886 159 5.48 %
Rwork0.2419 2742 -
all0.2443 2901 -
obs--99.76 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.067-0.63580.01942.0111-0.03181.98760.1022-0.00520.1024-0.1975-0.0884-0.25560.29150.5357-0.01380.09710.13880.0633-0.0245-0.0573-0.0894-25.9425-85.2395-25.3884
21.16340.34790.56841.05440.48942.0692-0.08430.03790.0912-0.25750.0713-0.0874-0.6830.36890.0130.3359-0.13560.0515-0.18040.0052-0.1606-35.1345-42.4686-14.3658
31.226-0.5492-0.64641.8850.04242.6784-0.08130.1664-0.1727-0.2259-0.0167-0.11620.92290.36920.0980.50360.3040.0687-0.29-0.0975-0.3515-23.4176-111.483-37.4846
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|13 - A|293 }A13 - 293
2X-RAY DIFFRACTION2{ A|294 - A|637 }A294 - 637
3X-RAY DIFFRACTION3{ B|21 - B|329 }B21 - 329

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