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- 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
TitleStructure of a minimal SF3B core in complex with the inactive modulator spliceostatin E (form I)
Components
  • (Splicing factor 3B subunit ...) x 3
  • PHD finger-like domain-containing protein 5A
KeywordsSPLICING / 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 / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / splicing factor binding / U2-type precatalytic spliceosome / U2-type spliceosomal complex / U2-type prespliceosome assembly ...mRNA Splicing - Minor Pathway / mRNA Splicing - Major Pathway / U11/U12 snRNP / B-WICH complex / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / splicing factor binding / U2-type precatalytic spliceosome / U2-type spliceosomal complex / U2-type prespliceosome assembly / SAGA complex / U2 snRNP / U2-type prespliceosome / positive regulation of transcription by RNA polymerase III / precatalytic spliceosome / spliceosomal complex assembly / positive regulation of transcription by RNA polymerase I / regulation of RNA splicing / mRNA Splicing - Minor Pathway / U2 snRNA binding / regulation of DNA repair / catalytic step 2 spliceosome / mRNA Splicing - Major Pathway / RNA splicing / stem cell differentiation / spliceosomal complex / mRNA splicing, via spliceosome / negative regulation of protein catabolic process / B-WICH complex positively regulates rRNA expression / nuclear matrix / nucleic acid binding / nuclear speck / chromatin remodeling / 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
Splicing factor 3B, subunit 5 / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 1 / PHF5-like / PHF5-like protein / Splicing factor 3B subunit 5/RDS3 complex subunit 10 / Splicing factor 3B subunit 10 (SF3b10) / Splicing factor 3B subunit 1-like / : / PPP2R1A-like HEAT repeat ...Splicing factor 3B, subunit 5 / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 1 / PHF5-like / PHF5-like protein / Splicing factor 3B subunit 5/RDS3 complex subunit 10 / Splicing factor 3B subunit 10 (SF3b10) / Splicing factor 3B subunit 1-like / : / PPP2R1A-like HEAT repeat / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Armadillo-like helical / Armadillo-type fold / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Spliceostatin E (form I) / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 3 / PHD finger-like domain-containing protein 5A / Splicing factor 3B subunit 3 / Splicing factor 3B subunit 5
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsCretu, C. / Pena, V.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)PE 2079/4-1 Germany
CitationJournal: 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
DepositionMay 31, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Splicing factor 3B subunit 3
B: Splicing factor 3B subunit 5
C: Splicing factor 3B subunit 1
D: PHD finger-like domain-containing protein 5A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,8148
Polymers219,1584
Non-polymers6564
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14960 Å2
ΔGint-62 kcal/mol
Surface area73760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.535, 108.280, 253.202
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Splicing factor 3B subunit ... , 3 types, 3 molecules ABC

#1: Protein Splicing factor 3B subunit 3 / Pre-mRNA-splicing factor SF3b 130 kDa subunit / SF3b130 / Spliceosome-associated protein 130 / SAP 130 /


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
#2: Protein Splicing factor 3B subunit 5 / SF3b5 / Pre-mRNA-splicing factor SF3b 10 kDa subunit


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 Splicing factor 3B subunit 1 / Pre-mRNA-splicing factor SF3b 155 kDa subunit / SF3b155 / Spliceosome-associated protein 155 / SAP 155


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

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Protein , 1 types, 1 molecules D

#4: Protein PHD finger-like domain-containing protein 5A / PHD finger-like domain protein 5A / Splicing factor 3B-associated 14 kDa protein / SF3b14b


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 / Spliceostatin E (form I) / [(Z,2S)-5-[[(2R,3R,5S,6S)-2,5-dimethyl-6-[(2E,4E)-3-methyl-5-[(2S)-4-methyl-6-oxidanylidene-2,3-dihydropyran-2-yl]penta-2,4-dienyl]oxan-3-yl]amino]-5-oxidanylidene-pent-3-en-2-yl] ethanoate / [(Z,2S)-5-[[(2R,3R,5S,6S)-2,5-dimethyl-6-[(2E,4E)-3-methyl-5-[(2S)-4-methyl-6-oxo-2,3-dihydropyran-2-yl]penta-2,4-dienyl]oxan-3-yl]amino]-5-oxopent-3-en-2-yl] acetate / 90123658


Mass: 459.575 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H37NO6 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn

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Details

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: 3.27 Å3/Da / Density % sol: 62.38 %
Crystal growTemperature: 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%

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 29, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 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 shellResolution: 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

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.19_4092refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IFE

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
RfactorNum. reflection% reflection
Rfree0.2694 4760 4.73 %
Rwork0.2281 95864 -
obs0.2299 52925 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 118.1 Å2
Refinement stepCycle: LAST / Resolution: 3.1→48.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14765 0 36 0 14801
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002615100
X-RAY DIFFRACTIONf_angle_d0.597120450
X-RAY DIFFRACTIONf_chiral_restr0.04362307
X-RAY DIFFRACTIONf_plane_restr0.00482647
X-RAY DIFFRACTIONf_dihedral_angle_d4.86672060
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.140.5041920.49273165X-RAY DIFFRACTION99.88
3.14-3.170.47181580.45663222X-RAY DIFFRACTION99.91
3.17-3.210.41061870.40583112X-RAY DIFFRACTION99.91
3.21-3.250.37241740.38823199X-RAY DIFFRACTION99.94
3.25-3.290.35661800.35263196X-RAY DIFFRACTION99.79
3.29-3.340.3461610.33313163X-RAY DIFFRACTION99.76
3.34-3.390.35121370.33113249X-RAY DIFFRACTION99.79
3.39-3.440.39271550.30673134X-RAY DIFFRACTION99.88
3.44-3.490.32721940.29353239X-RAY DIFFRACTION99.88
3.49-3.550.33581370.28593137X-RAY DIFFRACTION99.85
3.55-3.610.32511840.29023215X-RAY DIFFRACTION99.88
3.61-3.680.32361350.28613207X-RAY DIFFRACTION99.94
3.68-3.750.32391640.28453219X-RAY DIFFRACTION99.94
3.75-3.820.2771620.25763150X-RAY DIFFRACTION100
3.82-3.910.36451460.26043186X-RAY DIFFRACTION99.88
3.91-40.25941510.25763224X-RAY DIFFRACTION99.94
4-4.10.27411230.23093221X-RAY DIFFRACTION99.94
4.1-4.210.36121380.24063291X-RAY DIFFRACTION100
4.21-4.330.29281620.23173159X-RAY DIFFRACTION99.97
4.33-4.470.27651660.22933166X-RAY DIFFRACTION99.91
4.47-4.630.26171520.22123196X-RAY DIFFRACTION99.97
4.63-4.810.2881630.20863211X-RAY DIFFRACTION99.88
4.82-5.030.28141530.20373205X-RAY DIFFRACTION100
5.03-5.30.25751640.2133181X-RAY DIFFRACTION100
5.3-5.630.25341710.22563203X-RAY DIFFRACTION100
5.63-6.060.24011430.22473203X-RAY DIFFRACTION100
6.06-6.670.24861380.21683228X-RAY DIFFRACTION100
6.67-7.630.23742010.20583151X-RAY DIFFRACTION100
7.64-9.610.18981180.15623235X-RAY DIFFRACTION100
9.61-48.430.18971510.17173197X-RAY DIFFRACTION99.38

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