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- PDB-9c10: AMG 193, a clinical stage MTA-cooperative PRMT5 inhibitor, drives... -

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Basic information

Entry
Database: PDB / ID: 9c10
TitleAMG 193, a clinical stage MTA-cooperative PRMT5 inhibitor, drives anti-tumor activity preclinically and in patients with MTAP-deleted cancers
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PRMT5 / MTA-cooperative 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 / histone methyltransferase activity / regulation of mitotic nuclear division / negative regulation of gene expression via chromosomal CpG island methylation / Cul4B-RING E3 ubiquitin ligase complex / E-box binding / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / negative regulation of cell differentiation / spliceosomal snRNP assembly / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / ubiquitin-like ligase-substrate adaptor activity / 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 / 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 DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol
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. / 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 / WD40/YVTN repeat-like-containing domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
: / 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: 2.85 Å
AuthorsGhimire-Rijal, S. / Mukund, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cancer Discov / Year: 2025
Title: AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers.
Authors: Belmontes, B. / Slemmons, K.K. / Su, C. / Liu, S. / Policheni, A.N. / Moriguchi, J. / Tan, H. / Xie, F. / Aiello, D.A. / Yang, Y. / Lazaro, R. / Aeffner, F. / Rees, M.G. / Ronan, M.M. / ...Authors: Belmontes, B. / Slemmons, K.K. / Su, C. / Liu, S. / Policheni, A.N. / Moriguchi, J. / Tan, H. / Xie, F. / Aiello, D.A. / Yang, Y. / Lazaro, R. / Aeffner, F. / Rees, M.G. / Ronan, M.M. / Roth, J.A. / Vestergaard, M. / Cowland, S. / Andersson, J. / Sarvary, I. / Chen, Q. / Sharma, P. / Lopez, P. / Tamayo, N. / Pettus, L.H. / Ghimire-Rijal, S. / Mukund, S. / Allen, J.R. / DeVoss, J. / Coxon, A. / Rodon, J. / Ghiringhelli, F. / Penel, N. / Prenen, H. / Glad, S. / Chuang, C.H. / Keyvanjah, K. / Townsley, D.M. / Butler, J.R. / Bourbeau, M.P. / Caenepeel, S. / Hughes, P.E.
History
DepositionMay 28, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 27, 2024Group: Refinement description / Category: pdbx_initial_refinement_model / refine
Item: _pdbx_initial_refinement_model.accession_code / _pdbx_initial_refinement_model.details ..._pdbx_initial_refinement_model.accession_code / _pdbx_initial_refinement_model.details / _pdbx_initial_refinement_model.source_name / _pdbx_initial_refinement_model.type / _refine.pdbx_starting_model
Revision 1.3Jan 22, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year

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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)112,1697
Polymers111,1652
Non-polymers1,0045
Water84747
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.653, 138.157, 178.336
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 2 types, 2 molecules AB

#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: unidentified baculovirus
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: unidentified baculovirus / References: UniProt: Q9BQA1

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Non-polymers , 5 types, 52 molecules

#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-A1ATH / (4-amino-1,3-dihydrofuro[3,4-c][1,7]naphthyridin-8-yl){(3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl}methanone


Mass: 444.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H19F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-MTA / 5'-DEOXY-5'-METHYLTHIOADENOSINE


Mass: 297.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N5O3S
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 57.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 0.1M Na citrate tribasic dihydrate pH 5.6 2% Tascimate pH 5.0, 16% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 31, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→41.32 Å / Num. obs: 30217 / % possible obs: 99.8 % / Redundancy: 12.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.076 / Net I/σ(I): 24.6
Reflection shellResolution: 2.85→2.95 Å / Rmerge(I) obs: 0.076 / Mean I/σ(I) obs: 4.9 / Num. unique obs: 30217 / CC1/2: 0.999

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQB

4gqb


Resolution: 2.85→41.32 Å / SU ML: 0.4 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 36.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2993 1422 5 %
Rwork0.2605 --
obs0.2625 28439 93.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.85→41.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7294 0 68 47 7409
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077571
X-RAY DIFFRACTIONf_angle_d1.01610336
X-RAY DIFFRACTIONf_dihedral_angle_d18.7171012
X-RAY DIFFRACTIONf_chiral_restr0.0781141
X-RAY DIFFRACTIONf_plane_restr0.0071335
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.85-2.950.42931590.3542781X-RAY DIFFRACTION97
2.95-3.070.32621250.35122752X-RAY DIFFRACTION97
3.07-3.210.40651370.34242748X-RAY DIFFRACTION96
3.21-3.380.40991520.352650X-RAY DIFFRACTION93
3.38-3.590.41771420.3422223X-RAY DIFFRACTION79
3.59-3.870.42351350.35962485X-RAY DIFFRACTION87
3.87-4.260.29061280.24532622X-RAY DIFFRACTION91
4.26-4.870.23551450.21582822X-RAY DIFFRACTION98
4.87-6.130.2351290.22732922X-RAY DIFFRACTION99
6.14-41.320.23291700.19613012X-RAY DIFFRACTION100

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