National Research Council of Italy, Institute of Materials Foundry (CNR-IOM) c/o SISSA, Via Bonomea 265, 34136 Trieste, Italy.
National Institute of Chemistry, Theory Department, Hajdrihova 19, 1000 Ljubljana, Slovenia.
Int J Mol Sci. 2021 Oct 18;22(20):11222. doi: 10.3390/ijms222011222.
The SF3B1 protein, part of the SF3b complex, recognizes the intron branch point sequence of precursor messenger RNA (pre-mRNA), thus contributing to splicing fidelity. SF3B1 is frequently mutated in cancer and is the target of distinct families of splicing modulators (SMs). Among these, H3B-8800 is of particular interest, as it induces preferential lethality in cancer cells bearing the frequent and highly pathogenic K700E SF3B1 mutation. Despite the potential of H3B-8800 to treat myeloid leukemia and other cancer types hallmarked by SF3B1 mutations, the molecular mechanism underlying its preferential lethality towards spliceosome-mutant cancer cells remains elusive. Here, microsecond-long all-atom simulations addressed the binding/dissociation mechanism of H3B-8800 to wild type and K700E SF3B1-containing SF3b (SB3b) complexes at the atomic level, unlocking that the K700E mutation little affects the thermodynamics and kinetic traits of H3B-8800 binding. This supports the hypothesis that the selectivity of H3B-8800 towards mutant cancer cells is unrelated to its preferential targeting of SB3b. Nevertheless, this set of simulations discloses that the K700E mutation and H3B-8800 binding affect the overall SF3b internal motion, which in turn may influence the way SF3b interacts with other spliceosome components. Finally, we unveil the existence of a putative druggable SF3b pocket in the vicinity of K700E that could be harnessed in future rational drug-discovery efforts to specifically target mutant SF3b.
SF3B1 蛋白是 SF3b 复合物的一部分，它识别前体信使 RNA（pre-mRNA）的内含子分支点序列，从而有助于剪接保真度。SF3B1 在癌症中经常发生突变，是不同剪接调节剂（SM）家族的靶点。其中，H3B-8800 特别引人注目，因为它在携带高频且高度致病性 K700E SF3B1 突变的癌细胞中诱导优先致死性。尽管 H3B-8800 有潜力治疗骨髓性白血病和其他以 SF3B1 突变为特征的癌症类型，但它对剪接体突变癌细胞具有优先致死性的分子机制仍不清楚。在这里，微秒级别的全原子模拟从原子水平上解决了 H3B-8800 与野生型和含 K700E SF3B1 的 SF3b（SB3b）复合物的结合/解离机制，揭示了 K700E 突变对 H3B-8800 结合的热力学和动力学特性影响很小。这支持了这样一种假设，即 H3B-8800 对突变癌细胞的选择性与其对 SB3b 的优先靶向无关。然而，这组模拟揭示了 K700E 突变和 H3B-8800 结合会影响 SF3b 的整体内部运动，这反过来又可能影响 SF3b 与其他剪接体成分相互作用的方式。最后，我们揭示了在 K700E 附近存在一个假定的可药用 SF3b 口袋，这可能在未来的合理药物发现努力中被利用，以专门针对突变的 SF3b。
