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Recognition of single-stranded nucleic acids by small-molecule splicing modulators
Tang, Zhichao Akhter, Sana Ramprasad, Ankita Wang, Xiao Reibarkh, Mikhail Wang, Jinan Aryal, Sadikshya Thota, Srinivas S. Zhao, Junxing Douglas, Justin T.
Tang, Zhichao
Akhter, Sana
Ramprasad, Ankita
Wang, Xiao
Reibarkh, Mikhail
Wang, Jinan
Aryal, Sadikshya
Thota, Srinivas S.
Zhao, Junxing
Douglas, Justin T.
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Abstract
Risdiplam is the first approved small-molecule splicing modulator for the treatment of spinal muscular atrophy (SMA). Previous studies demonstrated that risdiplam analogues have two separate binding sites in exon 7 of the SMN2 pre-mRNA: (i) the 5′-splice site and (ii) an upstream purine (GA)-rich binding site. Importantly, the sequence of this GA-rich binding site significantly enhanced the potency of risdiplam analogues. In this report, we unambiguously determined that a known risdiplam analogue, SMN-C2, binds to single-stranded GA-rich RNA in a sequence-specific manner. The minimum required binding sequence for SMN-C2 was identified as GAAGGAAGG. We performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which captured spontaneous binding of a risdiplam analogue to the target nucleic acids. We uncovered, for the first time, a ligand-binding pocket formed by two sequential GAAG loop-like structures. The simulation findings were highly consistent with experimental data obtained from saturation transfer difference (STD) NMR and structure-affinity-relationship studies of the risdiplam analogues. Together, these studies illuminate us to understand the molecular basis of single-stranded purine-rich RNA recognition by small-molecule splicing modulators with an unprecedented binding mode.
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2021-07-20
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Oxford University Press
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Tang_2021.pdf
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Tang, Z., Akhter, S., Ramprasad, A., Wang, X., Reibarkh, M., Wang, J., Aryal, S., Thota, S. S., Zhao, J., Douglas, J. T., Gao, P., Holmstrom, E. D., Miao, Y., & Wang, J. (2021). Recognition of single-stranded nucleic acids by small-molecule splicing modulators. Nucleic acids research, 49(14), 7870–7883. https://doi.org/10.1093/nar/gkab602