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- PDB-7s1r: PRMT5/MEP50 crystal structure with MTA and a phthalazinone inhibi... -

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Basic information

Entry
Database: PDB / ID: 7s1r
TitlePRMT5/MEP50 crystal structure with MTA and a phthalazinone inhibitor bound (compound (M)-31)
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 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 H4R3 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 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 / 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. / 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 / Alpha Beta
Similarity search - Domain/homology
Chem-85E / 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: 2.1 Å
AuthorsGunn, R.J. / Thomas, N.C. / Lawson, J.D. / Ivetac, A. / Kulyk, S. / Smith, C.R. / 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 / Category: pdbx_database_related
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)112,3494
Polymers111,6262
Non-polymers7232
Water6,846380
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-16 kcal/mol
Surface area37550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.567, 138.372, 178.795
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
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-85E / {7-[(5M)-5-(1-cyano-3-fluoronaphthalen-2-yl)-1-methyl-1H-pyrazol-4-yl]-4-oxo-3,4-dihydrophthalazin-1-yl}methanaminium


Mass: 425.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18FN6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 380 / 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: 2.87 Å3/Da / Density % sol: 57.13 %
Crystal growTemperature: 281 K / Method: vapor diffusion
Details: 100 mM Sodium Citrate pH 5, 9% 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: 0.987 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 25, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 65436 / % possible obs: 87.2 % / Redundancy: 2.9 % / Biso Wilson estimate: 33.91 Å2 / CC1/2: 0.99 / Net I/σ(I): 13.9
Reflection shellResolution: 2→2.14 Å / Num. unique obs: 1905 / CC1/2: 0.67

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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: 2.1→46.81 Å / SU ML: 0.2597 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.7373
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2225 3320 5.08 %
Rwork0.1794 62090 -
obs0.1815 65410 87.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.53 Å2
Refinement stepCycle: LAST / Resolution: 2.1→46.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7359 0 32 380 7771
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01077600
X-RAY DIFFRACTIONf_angle_d1.017310363
X-RAY DIFFRACTIONf_chiral_restr0.06041137
X-RAY DIFFRACTIONf_plane_restr0.00681338
X-RAY DIFFRACTIONf_dihedral_angle_d15.62732739
LS refinement shellResolution: 2.1→2.13 Å
RfactorNum. reflection% reflection
Rfree0.2694 65 -
Rwork0.2576 1502 -
obs--50.43 %
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)
11.0845452431-0.3008821427220.2598671456051.373240560130.08954098795591.85660668143-0.0159791370228-0.0691019662238-0.06613991045570.0884049474328-0.02282936685-0.01346065500340.4292476918030.3840376352770.02470177264740.3694574386140.1580973928610.03654221871860.36527578427-0.03211135767030.288851519876-28.712154016-92.492053124-17.942919714
21.77648689251-0.489833245431-0.3029515519371.908151329610.4861246673751.843692747890.1347650559330.168513316220.198982749626-0.411153099895-0.0478326990023-0.321011685585-0.09802912324210.549697889656-0.08715873782750.320763424230.04884358595940.1108479522130.43002869289-0.0008838007956390.337987863221-23.369662113-74.7033848251-31.3325078113
31.068131487760.3791086645470.4623642151561.118306028750.3366744605841.50306971589-0.06174693800620.06282508767170.138481440512-0.1678885988260.0509671278437-0.134423842966-0.6393803688310.267612345858-0.006846820743890.440235707464-0.1177901890150.0481351953630.2475582296850.00786695120360.264691550858-36.0226447136-41.6244273999-14.4048095113
40.653678061401-0.612784306333-0.5617014759441.994278630361.118046229330.786986428728-0.109762918107-0.035031987223-0.3157885924350.04677109709590.0793841694959-0.4052019345240.7607261308710.439314479836-0.1426668743221.001430833330.6033080566950.09292072759990.664855555951-0.08480878682420.613028319434-14.5066176178-115.24749575-26.7667989391
50.5115178086020.297316176749-0.01271059222360.6823603878760.1552063648240.07332340761430.0346674411680.0423310092371-0.0789472490245-0.417354871248-0.0125538457011-0.371181760950.4731718967530.606573178379-0.0529486200050.7449884441760.3791551489820.1022309459590.697910014081-0.05353619177860.503770262915-17.1380828234-102.783308574-41.1372791075
60.906395684520.559774107866-0.5456896059060.812236437278-0.4800089345760.370197753920.03448295889790.511408831009-0.245978891209-0.390101792483-0.0971038320468-0.06712871966160.681976117056-0.1762737211190.000433561458120.8998363922230.200912809599-0.01251270736730.543039208849-0.1157045734080.426149079908-33.6090502843-105.940574934-47.3500170519
71.48606285641-0.327606472166-0.1928664632980.760365735587-0.01072205424810.029666087092-0.02421105231540.233282040539-0.505642614802-0.02986272411620.1081160769640.1448107362930.8596555023650.1533912044170.06994814404591.208301888690.2662613600040.05273138101110.464022127388-0.1320243991370.560213275553-32.3942206576-119.626419487-35.0636306039
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 13 through 156 )
2X-RAY DIFFRACTION2chain 'A' and (resid 157 through 306 )
3X-RAY DIFFRACTION3chain 'A' and (resid 307 through 637 )
4X-RAY DIFFRACTION4chain 'B' and (resid 19 through 89 )
5X-RAY DIFFRACTION5chain 'B' and (resid 90 through 196 )
6X-RAY DIFFRACTION6chain 'B' and (resid 197 through 241 )
7X-RAY DIFFRACTION7chain 'B' and (resid 242 through 329 )

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