+Open data
-Basic information
Entry | Database: PDB / ID: 6v0p | ||||||
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Title | PRMT5 complex bound to covalent PBM inhibitor BRD6711 | ||||||
Components |
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Keywords | SPLICING/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 / 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 / histone H4R3 methyltransferase activity / secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development ...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 / histone H4R3 methyltransferase activity / 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 / protein-arginine N-methyltransferase activity / methylosome / E-box binding / methyl-CpG binding / endothelial cell activation / histone H3 methyltransferase activity / positive regulation of mRNA splicing, via spliceosome / negative regulation of gene expression via chromosomal CpG island methylation / regulation of mitotic nuclear division / Cul4B-RING E3 ubiquitin ligase complex / histone methyltransferase complex / positive regulation of oligodendrocyte differentiation / histone methyltransferase activity / negative regulation of cell differentiation / ubiquitin-like ligase-substrate adaptor activity / ribonucleoprotein complex binding / regulation of ERK1 and ERK2 cascade / spliceosomal snRNP assembly / liver regeneration / nuclear receptor coactivator activity / regulation of signal transduction by p53 class mediator / methyltransferase activity / DNA-templated transcription termination / circadian regulation of gene expression / Regulation of TP53 Activity through Methylation / p53 binding / RMTs methylate histone arginines / protein polyubiquitination / transcription corepressor activity / snRNP Assembly / ubiquitin-dependent protein catabolic process / chromatin remodeling / protein heterodimerization activity / positive regulation of cell population proliferation / regulation of transcription by RNA polymerase II / chromatin / regulation of DNA-templated transcription / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å | ||||||
Authors | McMillan, B.J. / McKinney, D.C. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6v0p.cif.gz | 753.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6v0p.ent.gz | 601 KB | Display | PDB format |
PDBx/mmJSON format | 6v0p.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6v0p_validation.pdf.gz | 382.2 KB | Display | wwPDB validaton report |
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Full document | 6v0p_full_validation.pdf.gz | 383.2 KB | Display | |
Data in XML | 6v0p_validation.xml.gz | 1.7 KB | Display | |
Data in CIF | 6v0p_validation.cif.gz | 14 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/v0/6v0p ftp://data.pdbj.org/pub/pdb/validation_reports/v0/6v0p | HTTPS FTP |
-Related structure data
Related structure data | 7m05C 4gqbS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein , 2 types, 2 molecules AB
#1: Protein | 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 |
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#2: Protein | 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 |
-Non-polymers , 5 types, 643 molecules
#3: Chemical | ChemComp-QN4 / | ||||||
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#4: Chemical | #5: Chemical | ChemComp-SFG / | #6: Chemical | #7: Water | ChemComp-HOH / | |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.8 Å3/Da / Density % sol: 56.03 % |
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Crystal grow | Temperature: 281 K / Method: vapor diffusion, hanging drop / pH: 7.4 / Details: 26% PEG3350 200 mM ammonium sulfate 0.05% w/v DDM |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.979 Å |
Detector | Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 26, 2018 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.979 Å / Relative weight: 1 |
Reflection | Resolution: 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 shell | Resolution: 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 |
-Processing
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4GQB Resolution: 1.88→36.73 Å / Cross valid method: THROUGHOUT
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Displacement parameters | Biso mean: 45.03 Å2 | ||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.88→36.73 Å
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Refine LS restraints |
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