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Yorodumi- PDB-7opi: Structure of a minimal SF3B core in complex with the inactive mod... -
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-Basic information
Entry | Database: PDB / ID: 7opi | ||||||
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Title | Structure of a minimal SF3B core in complex with the inactive modulator spliceostatin E (form I) | ||||||
Components |
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Keywords | SPLICING / Spliceosome / spliceostatin E / splicing inhibitor | ||||||
Function / homology | Function and homology information : / : / mRNA Splicing - Minor Pathway / : / mRNA Splicing - Major Pathway / U11/U12 snRNP / B-WICH complex / splicing factor binding / U12-type spliceosomal complex / RNA splicing, via transesterification reactions ...: / : / mRNA Splicing - Minor Pathway / : / mRNA Splicing - Major Pathway / U11/U12 snRNP / B-WICH complex / splicing factor binding / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / U2-type precatalytic spliceosome / U2-type spliceosomal complex / U2-type prespliceosome assembly / U2 snRNP / SAGA complex / positive regulation of transcription by RNA polymerase III / U2-type prespliceosome / precatalytic spliceosome / positive regulation of transcription by RNA polymerase I / spliceosomal complex assembly / mRNA Splicing - Minor Pathway / regulation of RNA splicing / U2 snRNA binding / regulation of DNA repair / catalytic step 2 spliceosome / mRNA Splicing - Major Pathway / RNA splicing / negative regulation of protein catabolic process / stem cell differentiation / spliceosomal complex / B-WICH complex positively regulates rRNA expression / nuclear matrix / mRNA splicing, via spliceosome / chromatin remodeling / nuclear speck / mRNA binding / positive regulation of DNA-templated transcription / protein-containing complex binding / nucleolus / positive regulation of transcription by RNA polymerase II / DNA binding / RNA binding / zinc ion binding / nucleoplasm / nucleus Similarity search - Function | ||||||
Biological species | Mus musculus (house mouse) Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å | ||||||
Authors | Cretu, C. / Pena, V. | ||||||
Funding support | Germany, 1items
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Citation | Journal: Nat Commun / Year: 2021 Title: Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors. Authors: Constantin Cretu / Patricia Gee / Xiang Liu / Anant Agrawal / Tuong-Vi Nguyen / Arun K Ghosh / Andrew Cook / Melissa Jurica / Nicholas A Larsen / Vladimir Pena / Abstract: Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing ...Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7opi.cif.gz | 473.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7opi.ent.gz | 302.2 KB | Display | PDB format |
PDBx/mmJSON format | 7opi.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/op/7opi ftp://data.pdbj.org/pub/pdb/validation_reports/op/7opi | HTTPS FTP |
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-Related structure data
Related structure data | 7b0iC 7b91C 7b92C 7b9cC 7omfC 7onbC 5ifeS C: citing same article (ref.) S: Starting model for refinement |
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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
-Splicing factor 3B subunit ... , 3 types, 3 molecules ABC
#1: Protein | Mass: 100722.109 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse), (gene. exp.) Homo sapiens (human) Gene: Sf3b3, Kiaa0017, SF3B3, KIAA0017, SAP130 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q921M3, UniProt: Q15393 |
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#2: Protein | Mass: 10149.369 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SF3B5, SF3B10 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BWJ5 |
#3: Protein | Mass: 96615.734 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SF3B1, SAP155 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: O75533 |
-Protein , 1 types, 1 molecules D
#4: Protein | Mass: 11670.525 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PHF5A / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q7RTV0 |
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-Non-polymers , 2 types, 4 molecules
#5: Chemical | ChemComp-07I / |
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#6: Chemical |
-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: 3.27 Å3/Da / Density % sol: 62.38 % |
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Crystal grow | Temperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.15 Details: 0.1 M Bis-tris propane pH=7.15, 0.2 M KSCN, PEG-3350 11% (w/v), Glycerol (v/v) 10% |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å |
Detector | Type: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 29, 2019 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.9→49.78 Å / Num. obs: 64378 / % possible obs: 99.9 % / Redundancy: 13.5 % / Biso Wilson estimate: 115.29 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.024 / Rrim(I) all: 0.088 / Χ2: 1 / Net I/σ(I): 17.5 |
Reflection shell | Resolution: 2.9→2.97 Å / Redundancy: 13.8 % / Rmerge(I) obs: 3.87 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 4387 / CC1/2: 0.431 / Rpim(I) all: 1.069 / Rrim(I) all: 4.017 / Χ2: 0.96 / % possible all: 98.3 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 5IFE Resolution: 3.1→48.43 Å / SU ML: 0.5286 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 31.2264 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 118.1 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 3.1→48.43 Å
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Refine LS restraints |
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LS refinement shell |
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