9Z2W

CryoEM structure of human NSUN2(C271A) with SAH cross-linked to tRNA Lys(TTT) (No D-arm conformation)

This is a non-PDB format compatible entry.

Summary for 9Z2W

• Entry DOI: 10.2210/pdb9z2w/pdb
• EMDB information: 73780
• Descriptor: RNA cytosine C(5)-methyltransferase NSUN2, tRNA Lys(TTT), S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• Functional Keywords: transferase, methyltransferase, trna, complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 113200.52

Authors

Canepa, J.,Ruiz-Arroyo, V.M.,Nam, Y. (deposition date: 2025-11-05, release date: 2026-06-03, Last modification date: 2026-07-22)

Primary citation

Canepa, J.,Ruiz-Arroyo, V.M.,Schlamowitz, N.S.,Nam, Y.
Substrate selectivity of the human RNA m 5 C methyltransferase NSUN2.
Nature, 655:801-808, 2026

PubMed Abstract: Specific deposition of RNA modifications is important for regulating gene expression. 5-Methylcytosine (mC) is a common epitranscriptomic modification, and NSUN2 is a key enzyme responsible for mC methylation of various types of RNA. Dysregulation of NSUN2 is associated with numerous diseases, including cancers and neurological disorders. The versatility of NSUN2 complicates our understanding of its substrate specificity and molecular roles in biology and disease. Here we show how NSUN2 interacts with RNA substrates at distinct stages of its catalytic cycle to modify cytidines. Furthermore, we show the role of RNA structure in facilitating NSUN2 activity at multiple tRNA positions. We identify RNA duplexes surrounding the mC modification site as crucial recognition elements for methylation, which enabled us to derive a minimized substrate that captures the preferred features of an NSUN2 substrate-a dual-stem structure containing the CNNRR motif at the 5' end of the first stem. Insights into the mechanisms underlying substrate-specific NSUN2 enzymatic activity provide opportunities for understanding and therapeutically targeting NSUN2-dependent methylation. Overall, our work highlights the roles of RNA structure and sequence in defining substrate specificity and regulating RNA-modifying enzymes.

PubMed: 42203868
DOI: 10.1038/s41586-026-10582-9

Experimental method

ELECTRON MICROSCOPY (3.1 Å)