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TitleStructure-driven RNA remodeling underlies broad substrate recognition by NSUN2.
Journal, issue, pagesSci China Life Sci, Year 2026
Publish dateMay 26, 2026
AuthorsQian Hu / Wen Yang / Yunyun Yu / Ran Yi / Yutong Zhang / Leyuan Duan / Fudong Li / Kaiming Zhang / Qingguo Gong / Shanshan Li /
PubMed AbstractThe human RNA mC methyltransferase NSUN2 catalyzes site-specific cytosine methylation across diverse RNA substrates and thereby regulates a wide range of biological and physiological processes. ...The human RNA mC methyltransferase NSUN2 catalyzes site-specific cytosine methylation across diverse RNA substrates and thereby regulates a wide range of biological and physiological processes. However, the molecular basis by which NSUN2 achieves broad substrate recognition while maintaining catalytic specificity has remained unclear. Here, we determine structures of human NSUN2 in both substrate-free and substrate-bound states using X-ray crystallography and cryo-electron microscopy. Structures of NSUN2 in complex with multiple tRNA substrates reveal a structure-first, sequence-tolerant strategy in which NSUN2 actively remodels tRNA architecture, exposing the buried target cytosine and positioning it within the catalytic pocket for methyl transfer. This recognition strategy enables NSUN2 to accommodate diverse tRNA substrates through a largely conserved interaction interface. Together, our findings define the molecular principles underlying NSUN2-mediated RNA mC modification.
External linksSci China Life Sci / PubMed:42258135
MethodsEM (single particle)
Resolution3.3 - 3.9 Å
Structure data

68111

21zh

EMDB-68111, PDB-21zh:
Cryo-EM structure of NSUN2-tRNAlys-SAM
Method: EM (single particle) / Resolution: 3.9 Å

68138

22av

EMDB-68138, PDB-22av:
Cryo-EM structure of NSUN2-tRNATyr-SAM
Method: EM (single particle) / Resolution: 3.34 Å

68140

22ax

EMDB-68140, PDB-22ax:
Cryo-EM structure of NSUN2-pre-tRNALeu-SAM
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-SAM:
S-ADENOSYLMETHIONINE

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/RNA / tRNA / m5C RNA methyltransferase / NSUN2 / TRANSFERASE-RNA complex

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