6EN4

SF3b core in complex with a splicing modulator


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.08 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.233 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.

Cretu, C.Agrawal, A.A.Cook, A.Will, C.L.Fekkes, P.Smith, P.G.Luhrmann, R.Larsen, N.Buonamici, S.Pena, V.

(2018) Mol Cell 70: 265-273.e8

  • DOI: https://doi.org/10.1016/j.molcel.2018.03.011
  • Primary Citation of Related Structures:  
    6EN4

  • PubMed Abstract: 

    SF3B is a multi-protein complex essential for branch site (BS) recognition and selection during pre-mRNA splicing. Several splicing modulators with antitumor activity bind SF3B and thereby modulate splicing. Here we report the crystal structure of a human SF3B core in complex with pladienolide B (PB), a macrocyclic splicing modulator and potent inhibitor of tumor cell proliferation. PB stalls SF3B in an open conformation by acting like a wedge within a hinge, modulating SF3B's transition to the closed conformation needed to form the BS adenosine-binding pocket and stably accommodate the BS/U2 duplex. This work explains the structural basis for the splicing modulation activity of PB and related compounds, and reveals key interactions between SF3B and a common pharmacophore, providing a framework for future structure-based drug design.


  • Organizational Affiliation

    Research Group Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Splicing factor 3B subunit 31,209Homo sapiensMutation(s): 0 
Gene Names: SF3B3KIAA0017SAP130
UniProt & NIH Common Fund Data Resources
Find proteins for Q15393 (Homo sapiens)
Explore Q15393 
Go to UniProtKB:  Q15393
PHAROS:  Q15393
GTEx:  ENSG00000189091 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15393
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Splicing factor 3B subunit 585Homo sapiensMutation(s): 0 
Gene Names: SF3B5SF3B10
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BWJ5 (Homo sapiens)
Explore Q9BWJ5 
Go to UniProtKB:  Q9BWJ5
PHAROS:  Q9BWJ5
GTEx:  ENSG00000169976 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BWJ5
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Splicing factor 3B subunit 1852Homo sapiensMutation(s): 0 
Gene Names: SF3B1SAP155
UniProt & NIH Common Fund Data Resources
Find proteins for O75533 (Homo sapiens)
Explore O75533 
Go to UniProtKB:  O75533
PHAROS:  O75533
GTEx:  ENSG00000115524 
Entity Groups  
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UniProt GroupO75533
Sequence Annotations
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
PHD finger-like domain-containing protein 5A108Homo sapiensMutation(s): 0 
Gene Names: PHF5A
UniProt & NIH Common Fund Data Resources
Find proteins for Q7RTV0 (Homo sapiens)
Explore Q7RTV0 
Go to UniProtKB:  Q7RTV0
PHAROS:  Q7RTV0
GTEx:  ENSG00000100410 
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UniProt GroupQ7RTV0
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BGZ
Query on BGZ

Download Ideal Coordinates CCD File 
H [auth D][(2~{S},3~{S},4~{E},6~{S},7~{R},10~{R})-3,7-dimethyl-2-[(2~{E},4~{E},6~{S})-6-methyl-7-[(2~{R},3~{R})-3-[(2~{R},3~{S})-3-oxidanylpentan-2-yl]oxiran-2-yl]hepta-2,4-dien-2-yl]-7,10-bis(oxidanyl)-12-oxidanylidene-1-oxacyclododec-4-en-6-yl] ethanoate
C30 H48 O8
SDOUORKJIJYJNW-QHOUZYGJSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth D],
F [auth D],
G [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BGZ BindingDB:  6EN4 EC50: min: 0.86, max: 1 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.08 Å
  • R-Value Free: 0.266 
  • R-Value Work: 0.233 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.067α = 90
b = 154.568β = 90
c = 210.207γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Max Planck SocietyGermany--

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-20
    Type: Initial release
  • Version 1.1: 2024-01-17
    Changes: Data collection, Database references, Refinement description