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- PDB-6v0p: PRMT5 complex bound to covalent PBM inhibitor BRD6711 -

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Basic information

Entry
Database: PDB / ID: 6v0p
TitlePRMT5 complex bound to covalent PBM inhibitor BRD6711
Components
  • Methylosome protein 50
  • Protein arginine N-methyltransferase 5
KeywordsSPLICING/TRANSFERASE / methyltransferase / splicing / SDMA / epigenetic / SPLICING-TRANSFERASE complex
Function / homology
Function and homology information


positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / Golgi ribbon formation / peptidyl-arginine methylation / histone H4R3 methyltransferase activity / protein-arginine N-methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / methylosome ...positive regulation of adenylate cyclase-inhibiting dopamine receptor signaling pathway / peptidyl-arginine N-methylation / type II protein arginine methyltransferase / protein-arginine omega-N symmetric methyltransferase activity / Golgi ribbon formation / peptidyl-arginine methylation / histone H4R3 methyltransferase activity / protein-arginine N-methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / methylosome / positive regulation of rRNA processing / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / regulation of mitotic nuclear division / histone methyltransferase activity / negative regulation of gene expression via chromosomal CpG island methylation / positive regulation of oligodendrocyte differentiation / E-box binding / Cul4B-RING E3 ubiquitin ligase complex / histone methyltransferase complex / negative regulation of cell differentiation / regulation of ERK1 and ERK2 cascade / ribonucleoprotein complex binding / ubiquitin-like ligase-substrate adaptor activity / spliceosomal snRNP assembly / 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 / protein polyubiquitination / RMTs methylate histone arginines / p53 binding / transcription corepressor activity / snRNP Assembly / ubiquitin-dependent protein catabolic process / transcription coactivator activity / chromatin remodeling / protein heterodimerization activity / 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 / 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 / S-adenosyl-L-methionine-dependent methyltransferase superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-QN4 / SINEFUNGIN / Protein arginine N-methyltransferase 5 / Methylosome protein WDR77
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsMcMillan, B.J. / McKinney, D.C.
CitationJournal: J Med Chem / Year: 2021
Title: Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.
Authors: David C McKinney / Brian J McMillan / Matthew J Ranaghan / Jamie A Moroco / Merissa Brousseau / Zachary Mullin-Bernstein / Meghan O'Keefe / Patrick McCarren / Michael F Mesleh / Kathleen M ...Authors: David C McKinney / Brian J McMillan / Matthew J Ranaghan / Jamie A Moroco / Merissa Brousseau / Zachary Mullin-Bernstein / Meghan O'Keefe / Patrick McCarren / Michael F Mesleh / Kathleen M Mulvaney / Foxy Robinson / Ritu Singh / Besnik Bajrami / Florence F Wagner / Robert Hilgraf / Martin J Drysdale / Arthur J Campbell / Adam Skepner / David E Timm / Dale Porter / Virendar K Kaushik / William R Sellers / Alessandra Ianari /
Abstract: PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates ...PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed the formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.
History
DepositionNov 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 25, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 8, 2021Group: Advisory / Database references
Category: citation / citation_author ...citation / citation_author / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)110,4838
Polymers109,4902
Non-polymers9936
Water11,476637
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)441,93232
Polymers437,9598
Non-polymers3,97324
Water1448
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area34220 Å2
ΔGint-183 kcal/mol
Surface area132500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.110, 138.570, 178.430
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22

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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: 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: 36723.164 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

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Non-polymers , 5 types, 643 molecules

#3: Chemical ChemComp-QN4 / 2-(5-chloro-6-oxopyridazin-1(6H)-yl)-N-(4-methyl-3-sulfamoylphenyl)acetamide


Mass: 356.785 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13ClN4O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-SFG / SINEFUNGIN / ADENOSYL-ORNITHINE


Mass: 381.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H23N7O5
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 637 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.8 Å3/Da / Density % sol: 56.03 %
Crystal growTemperature: 281 K / Method: vapor diffusion, hanging drop / pH: 7.4 / Details: 26% PEG3350 200 mM ammonium sulfate 0.05% w/v DDM

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.88→45 Å / Num. obs: 50976 / % possible obs: 93.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 39.59 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.115 / Net I/σ(I): 32.7
Reflection shellResolution: 1.88→2.1 Å / Redundancy: 5.5 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1020 / CC1/2: 0.48 / Rrim(I) all: 1.6 / % possible all: 86

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Processing

Software
NameVersionClassification
XDSdata reduction
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GQB

4gqb


Resolution: 1.88→36.73 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflectionSelection details
Rfree0.23 --RANDOM
Rwork0.187 ---
obs-50976 93.9 %-
Displacement parametersBiso mean: 45.03 Å2
Refinement stepCycle: LAST / Resolution: 1.88→36.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7258 0 64 637 7959
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0147545
X-RAY DIFFRACTIONf_angle_d1.608110282
X-RAY DIFFRACTIONf_chiral_restr0.10351131
X-RAY DIFFRACTIONf_plane_restr0.011355
X-RAY DIFFRACTIONf_dihedral_angle_d17.45574516

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