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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; Gao, Philip; Holmstrom, Erik D; Miao, Yinglong; Wang, Jingxin.
Afiliação
  • Tang Z; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
  • Akhter S; Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66047, USA.
  • Ramprasad A; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
  • Wang X; Analytical Research & Development, Merck and Co., Inc., Kenilworth, NJ 07033, USA.
  • Reibarkh M; Analytical Research & Development, Merck and Co., Inc., Kenilworth, NJ 07033, USA.
  • Wang J; Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66047, USA.
  • Aryal S; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
  • Thota SS; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
  • Zhao J; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
  • Douglas JT; Nuclear Magnetic Resonance Lab, University of Kansas, Lawrence, KS 66045, USA.
  • Gao P; Protein Production Group, University of Kansas, Lawrence, KS 66047, USA.
  • Holmstrom ED; Department of Molecular Biosciences and Department of Chemistry, University of Kansas, Lawrence, KS 66045, USA.
  • Miao Y; Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66047, USA.
  • Wang J; Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66047, USA.
Nucleic Acids Res ; 49(14): 7870-7883, 2021 08 20.
Article em En | MEDLINE | ID: mdl-34283224
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Compostos Azo / Atrofia Muscular Espinal / Precursores de RNA / Splicing de RNA Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Compostos Azo / Atrofia Muscular Espinal / Precursores de RNA / Splicing de RNA Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2021 Tipo de documento: Article