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- PDB-7ses: PRMT5/MEP50 with compound 29 bound -

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Basic information

Entry
Database: PDB / ID: 7ses
TitlePRMT5/MEP50 with compound 29 bound
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-97X / 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: 2.5 Å
AuthorsGunn, R.J. / Thomas, N.C. / Lawson, J.D. / Ivetac, A. / Smith, C.R. / Kulyk, S. / 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
DepositionOct 1, 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)112,3304
Polymers111,6262
Non-polymers7042
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4740 Å2
ΔGint-12 kcal/mol
Surface area38070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.783, 138.053, 179.034
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-97X / (2P)-2-{4-[4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl]-1-methyl-1H-pyrazol-5-yl}naphthalene-1-carbonitrile


Mass: 406.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18N6O / 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.: 46 / 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: 2.9 Å3/Da / Density % sol: 57.59 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 100 mM Sodium Citrate pH 5, 10% PEG 4K, 50 mM Sodium Acetate (pH 7)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: May 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 42618 / % possible obs: 93.9 % / Redundancy: 2.8 % / Biso Wilson estimate: 49.87 Å2 / Rpim(I) all: 0.06 / Net I/σ(I): 10.2
Reflection shellResolution: 2.5→2.54 Å / Num. unique obs: 2048 / CC1/2: 0.85 / Rpim(I) all: 0.29

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7S0U

7s0u


Resolution: 2.5→47.25 Å / SU ML: 0.3325 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 27.642
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2449 2148 5.04 %
Rwork0.2098 40446 -
obs0.2116 42594 93.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 63.48 Å2
Refinement stepCycle: LAST / Resolution: 2.5→47.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7361 0 51 46 7458
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00227622
X-RAY DIFFRACTIONf_angle_d0.526510391
X-RAY DIFFRACTIONf_chiral_restr0.04391140
X-RAY DIFFRACTIONf_plane_restr0.00391342
X-RAY DIFFRACTIONf_dihedral_angle_d11.33742775
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.550.37511280.33632551X-RAY DIFFRACTION89.84
2.55-2.620.34241440.30692697X-RAY DIFFRACTION94.54
2.62-2.690.31041630.28092705X-RAY DIFFRACTION95.95
2.69-2.770.2751370.27212771X-RAY DIFFRACTION96.48
2.77-2.860.32111450.25592546X-RAY DIFFRACTION91.1
2.86-2.960.31231410.26012848X-RAY DIFFRACTION99.2
2.96-3.080.28841680.26512790X-RAY DIFFRACTION98.44
3.08-3.220.30081410.23252807X-RAY DIFFRACTION98.07
3.22-3.390.26361300.22932803X-RAY DIFFRACTION96.89
3.39-3.60.21831380.22342690X-RAY DIFFRACTION94.42
3.6-3.880.27141420.21872680X-RAY DIFFRACTION92.4
3.88-4.270.22851320.18422435X-RAY DIFFRACTION85.11
4.27-4.880.21171610.16062650X-RAY DIFFRACTION92.38
4.89-6.150.20371510.17372766X-RAY DIFFRACTION94.07
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)
10.208303854209-0.117137071768-0.2070473490180.433540766848-0.03383384124170.7264671041850.023358699558-0.0729528733924-0.04802006482080.08793094751010.009494479038250.07362351722750.2465838345760.176514275347-5.90764704233E-60.3834408349350.108403803020.01589696976640.435945928497-0.04884754872080.396945286293-29.2852032633-92.9967654298-17.7564462436
20.207273820598-0.1890673572850.0245868945420.1469473926330.02512938212150.06020230786730.1144474315920.142424314728-0.0586269783976-0.267694221978-0.159986881984-0.03890075607680.04608884886820.0541546525272-3.45469989464E-50.4854304174560.09948428280450.03267741274680.512310393226-0.06575613401470.475346538495-34.8316862041-79.7331650554-33.6577232141
30.3246998713620.478706359807-0.1607016777020.601010962061-0.2160665968950.4377708434770.01772370301680.2292804331180.244304118703-0.2848151053880.138370031539-0.173172968088-0.0810156029590.1511045764529.14024486538E-60.3778692321960.03142219868760.1108541835060.5918298458020.001081565798860.539252109125-17.576599154-71.8110936802-29.1903070216
40.9948781593520.448807756710.5154602325080.6809142574910.316671746680.9008033858860.005156149522810.126179978123-0.0300494504683-0.04007589455360.0641506137194-0.0273777364232-0.3248788659580.181973997802-0.0001476601142280.454116934039-0.08039484153170.02974868204180.3766116202710.001568045192330.411762355264-36.6164502709-41.5895877409-14.3664820101
50.316935188164-0.101290531672-0.01970704128620.160424457607-0.113422088930.06983135259720.03522660983730.0533838776991-0.0699423164851-0.0681105083231-0.0410240722563-0.08031266301020.3471058739120.2605024101468.092400969E-60.8345373239120.3560418926060.05804990464210.69124062074-0.06672005345640.629493573306-15.0491970963-115.755170969-25.596912371
60.1838580119230.1648852530960.3407565764730.3156271588440.07849603898830.622473533898-0.02088417532790.1071142811270.00812227254138-0.2568523072590.0425225169157-0.1381156300560.1878959883390.2234972117170.0001342020077440.6017497993250.2406248085280.08513153249380.644923467311-0.06635770128220.503604492579-17.7709704362-103.332131606-40.7958887152
70.0994851311938-0.09927279893830.0427107782070.117950386683-0.01878586856890.071620208133-0.01313899173040.549639662401-0.0366702128566-0.07836775079050.0257707794529-0.2720410988070.351842120272-0.21188192096-1.86360351848E-50.7247294646880.1178064871380.009818986556430.705322755453-0.123011498450.508463511284-34.4902310575-105.810206215-47.275202278
80.6241418641810.225039835012-0.1506096109820.145955739921-0.1094832145550.0371154205341-0.2237098204820.200653501225-0.3187646325560.1117496397650.2119638197120.1199885638640.5436594028480.08104797588292.06819646907E-50.8657839659740.1453443835210.04954106385420.600119525534-0.1179512900310.575990455826-33.3630048049-119.327272832-35.4935976439
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 13 through 149 )AA13 - 1491 - 137
22chain 'A' and (resid 150 through 208 )AA150 - 208138 - 196
33chain 'A' and (resid 209 through 306 )AA209 - 306197 - 294
44chain 'A' and (resid 307 through 637 )AA307 - 637295 - 625
55chain 'B' and (resid 19 through 82 )BD19 - 821 - 64
66chain 'B' and (resid 83 through 196 )BD83 - 19665 - 178
77chain 'B' and (resid 197 through 241 )BD197 - 241179 - 220
88chain 'B' and (resid 242 through 329 )BD242 - 329221 - 305

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