6en4

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SF3b core in complex with a splicing modulator

Structural highlights

6en4 is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	5ife
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PHF5A_HUMAN] Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha. Also involved in pre-mRNA splicing.^[1] [SF3B3_HUMAN] Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron. [SF3B1_HUMAN] Subunit of the splicing factor SF3B required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the 'E' complex. Belongs also to the minor U12-dependent spliceosome, which is involved in the splicing of rare class of nuclear pre-mRNA intron.

Publication Abstract from PubMed

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.

Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.,Cretu C, Agrawal AA, Cook A, Will CL, Fekkes P, Smith PG, Luhrmann R, Larsen N, Buonamici S, Pena V Mol Cell. 2018 Apr 19;70(2):265-273.e8. doi: 10.1016/j.molcel.2018.03.011. Epub, 2018 Apr 12. PMID:29656923^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Will CL, Urlaub H, Achsel T, Gentzel M, Wilm M, Luhrmann R. Characterization of novel SF3b and 17S U2 snRNP proteins, including a human Prp5p homologue and an SF3b DEAD-box protein. EMBO J. 2002 Sep 16;21(18):4978-88. PMID:12234937
↑ Cretu C, Agrawal AA, Cook A, Will CL, Fekkes P, Smith PG, Luhrmann R, Larsen N, Buonamici S, Pena V. Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds. Mol Cell. 2018 Apr 19;70(2):265-273.e8. doi: 10.1016/j.molcel.2018.03.011. Epub, 2018 Apr 12. PMID:29656923 doi:http://dx.doi.org/10.1016/j.molcel.2018.03.011