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TitleStructural basis of intron selection by U2 snRNP in the presence of covalent inhibitors.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 4491, Year 2021
Publish dateJul 23, 2021
AuthorsConstantin Cretu / Patricia Gee / Xiang Liu / Anant Agrawal / Tuong-Vi Nguyen / Arun K Ghosh / Andrew Cook / Melissa Jurica / Nicholas A Larsen / Vladimir Pena /
PubMed AbstractIntron 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.
External linksNat Commun / PubMed:34301950 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.4 - 3.1 Å
Structure data

EMDB-12994, PDB-7onb:
Structure of the U2 5' module of the A3'-SSA complex
Method: EM (single particle) / Resolution: 3.1 Å

PDB-7b0i:
Structure of a minimal SF3B core in complex with spliceostatin A (form II)
Method: X-RAY DIFFRACTION / Resolution: 3 Å

PDB-7b91:
Structure of a minimal SF3B core in complex with pladienolide D (form I)
Method: X-RAY DIFFRACTION / Resolution: 3 Å

PDB-7b92:
Structure of a minimal SF3B core in complex with sudemycin D6 (form II)
Method: X-RAY DIFFRACTION / Resolution: 3 Å

PDB-7b9c:
Structure of a minimal SF3B core in complex with spliceostatin A (form I)
Method: X-RAY DIFFRACTION / Resolution: 2.4 Å

PDB-7omf:
Structure of a minimal SF3B core in complex with sudemycin D6 (form I)
Method: X-RAY DIFFRACTION / Resolution: 3 Å

PDB-7opi:
Structure of a minimal SF3B core in complex with the inactive modulator spliceostatin E (form I)
Method: X-RAY DIFFRACTION / Resolution: 3.1 Å

Chemicals

ChemComp-SJT:
spliceostatin A (form II)

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-T2Z:
[(2~{S},3~{S},4~{E},6~{S},7~{R},10~{R})-3,7-dimethyl-2-[(2~{E},4~{E},6~{R})-6-methyl-6-oxidanyl-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

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

ChemComp-SCN:
THIOCYANATE ION

ChemComp-07I:
Spliceostatin E (form I)

Source
  • homo sapiens (human)
  • unidentified adenovirus
  • human (human)
  • mus musculus (house mouse)
KeywordsSPLICING / SF3B / pre-mRNA splicing / splicing modulator / spliceostatin A / pladienolide D / sudemycin D6 / Splicing inhibitor / SF3B complex / Spliceosome / spliceostatin E

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