Journal
COMMUNICATIONS BIOLOGY
Volume 4, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-021-02890-9
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Funding
- National Natural Science Foundation of China [31870782, 31822015]
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This study reports the crystal structure of human m3C methyltransferase METTL6, generating structure models of hMETTL6 in complex with substrates. The findings provide important insights into the molecular recognition mechanism by METTL6 and may aid in METTL-based rational drug design in the future.
In tRNA, the epigenetic m(3)C modification at position 32 in the anticodon loop is highly conserved in eukaryotes, which maintains the folding and basepairing functions of the anticodon. However, the responsible enzymes METTL2 and METTL6 were identified only in recent years. The loss of human METTL6 (hMETTL6) affects the translational process and proteostasis in cells, while in mESCs cells, it leads to defective pluripotency potential. Despite its important functions, the catalytic mechanism of the C32 methylation by this enzyme is poorly understood. Here we present the 1.9 angstrom high-resolution crystal structure of hMETTL6 bound by SAH. The key residues interacting with the ligand were identified and their roles were confirmed by ITC. We generated a docking model for the hMETTL6-SAH-CMP ternary complex. Interestingly, the CMP molecule binds into a cavity in a positive patch with the base ring pointing to the inside, suggesting a flipped-base mechanism for methylation. We further generated a model for the quaternary complex with tRNA(Ser) as a component, which reasonably explained the biochemical behaviors of hMETTL6. Taken together, our crystallographic and biochemical studies provide important insight into the molecular recognition mechanism by METTL6 and may aid in the METTL-based rational drug design in the future. Ran Chen et al. report the crystal structure of human m3C methyltrasfease METTL6. They generate structure models of hMETTL6 in complex with substrates, providing important insight into the molecular recognition mechanism by METTL6 and may aid in the METTL-based rational drug design in the future.
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