6EN4

SF3b core in complex with a splicing modulator

Summary for 6EN4

• Entry DOI: 10.2210/pdb6en4/pdb
• Related: 5IFE
• Descriptor: Splicing factor 3B subunit 3, Splicing factor 3B subunit 5, Splicing factor 3B subunit 1, ... (6 entities in total)
• Functional Keywords: protein complex, splicing modulator, splicing
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 254056.34

Authors

Cretu, C.,Pena, V. (deposition date: 2017-10-04, release date: 2018-06-20, Last modification date: 2024-01-17)

Primary citation

Cretu, C.,Agrawal, A.A.,Cook, A.,Will, C.L.,Fekkes, P.,Smith, P.G.,Luhrmann, R.,Larsen, N.,Buonamici, S.,Pena, V.
Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.
Mol. Cell, 70:265-273.e8, 2018

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.

PubMed: 29656923
DOI: 10.1016/j.molcel.2018.03.011

Experimental method

X-RAY DIFFRACTION (3.08 Å)