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Nat Commun. 2014;5:3004. doi: 10.1038/ncomms4004.

Structural analysis of human 2'-O-ribose methyltransferases involved in mRNA cap structure formation.

Author information

1
1] Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. ks. Trojdena 4, PL-02-109 Warsaw, Poland [2] Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, ul. ks. Trojdena 4, PL-02-109 Warsaw, Poland.
2
Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. ks. Trojdena 4, PL-02-109 Warsaw, Poland.
3
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, ul. Zwirki i Wigury 93, PL-02-089 Warsaw, Poland.
4
1] Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, ul. Zwirki i Wigury 93, PL-02-089 Warsaw, Poland [2] Centre of New Technologies, University of Warsaw, ul. Zwirki i Wigury 93, PL-02-089 Warsaw, Poland.
5
Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, ul. ks. Trojdena 4, PL-02-109 Warsaw, Poland.
6
1] Laboratory of Bioinformatics and Protein Engineering, International Institute of Molecular and Cell Biology in Warsaw, ul. ks. Trojdena 4, PL-02-109 Warsaw, Poland [2] Laboratory of Bioinformatics, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, ul. Umultowska 89, PL-61-614 Poznan, Poland.

Abstract

The 5' cap of human messenger RNA contains 2'-O-methylation of the first and often second transcribed nucleotide that is important for its processing, translation and stability. Human enzymes that methylate these nucleotides, termed CMTr1 and CMTr2, respectively, have recently been identified. However, the structures of these enzymes and their mechanisms of action remain unknown. In the present study, we solve the crystal structures of the active CMTr1 catalytic domain in complex with a methyl group donor and a capped oligoribonucleotide, thereby revealing the mechanism of specific recognition of capped RNA. This mechanism differs significantly from viral enzymes, thus providing a framework for their specific targeting. Based on the crystal structure of CMTr1, a comparative model of the CMTr2 catalytic domain is generated. This model, together with mutational analysis, leads to the identification of residues involved in RNA and methyl group donor binding.

PMID:
24402442
PMCID:
PMC3941023
DOI:
10.1038/ncomms4004
[Indexed for MEDLINE]
Free PMC Article

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