Structural insights into the decoding capability of isoleucine tRNAs with lysidine and agmatidine

• Published in: Nature structural & molecular biology Vol. 31; no. 5; pp. 817 - 825
• Main Authors: Akiyama, Naho, Ishiguro, Kensuke, Yokoyama, Takeshi, Miyauchi, Kenjyo, Nagao, Asuteka, Shirouzu, Mikako, Suzuki, Tsutomu
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2024; Nature Publishing Group
• Subjects: 631/337/1645/2570; 631/337/574/1789; 631/337/574/1793; 631/535/1258/1259; Adenine; Anticodon - chemistry; Anticodon - metabolism; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Codon - genetics; Cryoelectron Microscopy; Cytidine - analogs & derivatives; Cytidine - chemistry; Cytidine - metabolism; Electron microscopy; Hydrogen bonding; Hydrogen bonds; Isoleucine; Life Sciences; Lysine - analogs & derivatives; Lysine - chemistry; Lysine - metabolism; Membrane Biology; Models, Molecular; mRNA; Nucleic Acid Conformation; Protein Biosynthesis; Protein Structure; Protein synthesis; Pyrimidine Nucleosides; Residues; Ribonucleic acid; Ribosomes - chemistry; Ribosomes - metabolism; RNA; RNA, Transfer - chemistry; RNA, Transfer - genetics; RNA, Transfer - metabolism; RNA, Transfer, Ile - chemistry; RNA, Transfer, Ile - genetics; RNA, Transfer, Ile - metabolism; Transfer RNA; tRNA; tRNA Ala
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-024-01238-1

The anticodon modifications of transfer RNAs (tRNAs) finetune the codon recognition on the ribosome for accurate translation. Bacteria and archaea utilize the modified cytidines, lysidine (L) and agmatidine (agm 2 C), respectively, in the anticodon of tRNA Ile to decipher AUA codon. L and agm 2 C contain long side chains with polar termini, but their functions remain elusive. Here we report the cryogenic electron microscopy structures of tRNAs Ile recognizing the AUA codon on the ribosome. Both modifications interact with the third adenine of the codon via a unique C–A geometry. The side chains extend toward 3′ direction of the mRNA, and the polar termini form hydrogen bonds with 2′-OH of the residue 3′-adjacent to the AUA codon. Biochemical analyses demonstrated that AUA decoding is facilitated by the additional interaction between the polar termini of the modified cytidines and 2′-OH of the fourth mRNA residue. We also visualized cyclic N 6 -threonylcarbamoyladenosine (ct 6 A), another tRNA modification, and revealed a molecular basis how ct 6 A contributes to efficient decoding. Precise protein synthesis is achieved by tRNA modifications. Here the authors revealed that modified cytidines in tRNA Ile use their long side chains to make additional interactions with mRNA for stable tRNA binding on the ribosome.