dc.contributor.author | Tang, Zhichao | |
dc.contributor.author | Akhter, Sana | |
dc.contributor.author | Ramprasad, Ankita | |
dc.contributor.author | Wang, Xiao | |
dc.contributor.author | Reibarkh, Mikhail | |
dc.contributor.author | Wang, Jinan | |
dc.contributor.author | Aryal, Sadikshya | |
dc.contributor.author | Thota, Srinivas S. | |
dc.contributor.author | Zhao, Junxing | |
dc.contributor.author | Douglas, Justin T. | |
dc.contributor.author | Gao, Philip | |
dc.contributor.author | Holmstrom, Erik D. | |
dc.contributor.author | Miao, Yinglong | |
dc.contributor.author | Wang, Jingxin | |
dc.date.accessioned | 2021-12-03T21:10:21Z | |
dc.date.available | 2021-12-03T21:10:21Z | |
dc.date.issued | 2021-07-20 | |
dc.identifier.citation | 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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/32253 | |
dc.description.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. | en_US |
dc.publisher | Oxford University Press | en_US |
dc.rights | © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.title | Recognition of single-stranded nucleic acids by small-molecule splicing modulators | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Tang, Zhichao | |
kusw.kuauthor | Akhter, Sana | |
kusw.kuauthor | Ramprasad, Ankita | |
kusw.kuauthor | Wang, Jinan | |
kusw.kuauthor | Aryal, Sadikshya | |
kusw.kuauthor | Thota, Srinivas S. | |
kusw.kuauthor | Zhao, Junxing | |
kusw.kuauthor | Douglas, Justin T. | |
kusw.kuauthor | Gao, Philip | |
kusw.kuauthor | Holmstrom, Erik D. | |
kusw.kuauthor | Miao, Yinglong | |
kusw.kuauthor | Wang, Jingxin | |
kusw.kudepartment | Medicinal Chemistry | en_US |
kusw.kudepartment | Center for Computational Biology | en_US |
kusw.kudepartment | Molecular Biosciences | en_US |
dc.identifier.doi | 10.1093/nar/gkab602 | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0003-2624-0806 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC8373063 | en_US |
dc.rights.accessrights | openAccess | en_US |