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- PDB-7b92: Structure of a minimal SF3B core in complex with sudemycin D6 (fo... -

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Basic information

Entry
Database: PDB / ID: 7b92
TitleStructure of a minimal SF3B core in complex with sudemycin D6 (form II)
Components
  • (Splicing factor 3B subunit ...) x 3
  • PHD finger-like domain-containing protein 5A
KeywordsSPLICING / SF3B / pre-mRNA splicing / splicing modulator / sudemycin D6
Function / homology
Function and homology information


U11/U12 snRNP / B-WICH complex / splicing factor binding / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / U2-type spliceosomal complex / U2-type precatalytic spliceosome / : / U2-type prespliceosome assembly / U2 snRNP ...U11/U12 snRNP / B-WICH complex / splicing factor binding / U12-type spliceosomal complex / RNA splicing, via transesterification reactions / U2-type spliceosomal complex / U2-type precatalytic spliceosome / : / U2-type prespliceosome assembly / U2 snRNP / SAGA complex / positive regulation of transcription by RNA polymerase III / U2-type prespliceosome / precatalytic spliceosome / spliceosomal complex assembly / positive regulation of transcription by RNA polymerase I / 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 / stem cell differentiation / spliceosomal complex / B-WICH complex positively regulates rRNA expression / negative regulation of protein catabolic process / mRNA splicing, via spliceosome / nuclear matrix / nuclear speck / chromatin remodeling / mRNA binding / protein-containing complex binding / nucleolus / positive regulation of DNA-templated transcription / 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 / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term ...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 / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / CPSF A subunit region / Armadillo-like helical / Armadillo-type fold / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-T2W / Splicing factor 3B subunit 1 / Splicing factor 3B subunit 3 / PHD finger-like domain-containing protein 5A / Splicing factor 3B subunit 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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
DepositionDec 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 2.0Jan 31, 2024Group: Data collection / Database references ...Data collection / Database references / Non-polymer description / Refinement description
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.formula / _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)219,8318
Polymers219,1584
Non-polymers6734
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area15490 Å2
ΔGint-102 kcal/mol
Surface area72590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.429, 107.429, 361.474
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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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 / STAF130 / Spliceosome-associated protein ...Pre-mRNA-splicing factor SF3b 130 kDa subunit / SF3b130 / STAF130 / 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.) Homo sapiens (human) / Gene: SF3B3, KIAA0017, SAP130 / Production host: Trichoplusia ni (cabbage looper) / References: 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 , 3 types, 5 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-T2W / [(~{Z},2~{S})-5-[[4-[(2~{E},4~{E})-3-methyl-5-[(2~{S},4~{R})-4,6,6-trimethyl-4-oxidanyl-oxan-2-yl]penta-2,4-dienyl]cyclohexyl]amino]-5-oxidanylidene-pent-3-en-2-yl] ~{N}-methylcarbamate


Mass: 476.649 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H44N2O5 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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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: 2.75 Å3/Da / Density % sol: 55.23 % / Description: Dome-shaped crystals
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES pH=7.42, 0.2 M Magnesium chloride, 27.75% (v/v) PEG-400

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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 PILATUS 6M-F / Detector: PIXEL / Date: Feb 22, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→49.06 Å / Num. obs: 49623 / % possible obs: 100 % / Redundancy: 20.8 % / Biso Wilson estimate: 106.3 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.181 / Rpim(I) all: 0.041 / Rrim(I) all: 0.185 / Net I/σ(I): 14.7
Reflection shellResolution: 3→3.1 Å / Redundancy: 21.3 % / Rmerge(I) obs: 4.108 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 4468 / CC1/2: 0.367 / Rpim(I) all: 0.907 / Rrim(I) all: 4.208 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.17.1_3660refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IFE, 6EN4

5ife

6en4


Resolution: 3→46.52 Å / SU ML: 0.6037 / Cross valid method: FREE R-VALUE / σ(F): 0.31 / Phase error: 31.3844
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2583 4564 4.95 %
Rwork0.2234 87721 -
obs0.2251 48978 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 102.24 Å2
Refinement stepCycle: LAST / Resolution: 3→46.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14754 0 37 1 14792
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002515090
X-RAY DIFFRACTIONf_angle_d0.536720439
X-RAY DIFFRACTIONf_chiral_restr0.04122304
X-RAY DIFFRACTIONf_plane_restr0.00392641
X-RAY DIFFRACTIONf_dihedral_angle_d22.87262059
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.030.42851400.40062725X-RAY DIFFRACTION93.75
3.03-3.070.43451680.39542944X-RAY DIFFRACTION97.68
3.07-3.110.37141290.39362850X-RAY DIFFRACTION98.38
3.11-3.150.37451620.37162968X-RAY DIFFRACTION98.86
3.15-3.190.40261320.35992915X-RAY DIFFRACTION98.83
3.19-3.230.43031700.3682910X-RAY DIFFRACTION98.94
3.23-3.280.41431200.35772963X-RAY DIFFRACTION99.23
3.28-3.330.38681560.36312931X-RAY DIFFRACTION99.29
3.33-3.380.35781540.31962967X-RAY DIFFRACTION99.68
3.38-3.430.3811500.32692922X-RAY DIFFRACTION99.93
3.43-3.490.37921900.30492942X-RAY DIFFRACTION99.87
3.49-3.560.29741940.27552933X-RAY DIFFRACTION99.68
3.56-3.630.3231800.27942907X-RAY DIFFRACTION99.94
3.63-3.70.31591400.27363004X-RAY DIFFRACTION99.59
3.7-3.780.32861500.27082862X-RAY DIFFRACTION99.54
3.78-3.870.30481620.26293008X-RAY DIFFRACTION99.81
3.87-3.960.26221670.24552950X-RAY DIFFRACTION99.78
3.97-4.070.34041470.24892925X-RAY DIFFRACTION99.74
4.07-4.190.28631220.222949X-RAY DIFFRACTION99.81
4.19-4.330.19521320.20733044X-RAY DIFFRACTION99.94
4.33-4.480.22531440.18812951X-RAY DIFFRACTION99.77
4.48-4.660.2221580.18992974X-RAY DIFFRACTION99.94
4.66-4.870.23831440.18722906X-RAY DIFFRACTION99.84
4.87-5.130.19941560.18742956X-RAY DIFFRACTION100
5.13-5.450.26951400.19732982X-RAY DIFFRACTION99.74
5.45-5.870.24841550.20512928X-RAY DIFFRACTION99.84
5.87-6.460.21641590.20922944X-RAY DIFFRACTION99.74
6.46-7.390.22681580.18722941X-RAY DIFFRACTION99.65
7.39-9.30.19351350.1722867X-RAY DIFFRACTION96.34
9.3-46.520.19361500.16442653X-RAY DIFFRACTION89.81

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