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RNA primer-template complex with guanosine dinucleotide p(5')G(3')p(5')G ligand
Structural highlights
Publication Abstract from PubMedThe nonenzymatic copying of RNA templates with imidazole-activated nucleotides is a well-studied model for the emergence of RNA self-replication during the origin of life. We have recently discovered that this reaction can proceed through the formation of an imidazolium-bridged dinucleotide intermediate that reacts rapidly with the primer. To gain insight into the relationship between the structure of this intermediate and its reactivity, we cocrystallized an RNA primer-template complex with a close analog of the intermediate, the triphosphate-bridged guanosine dinucleotide GpppG, and solved a high-resolution X-ray structure of the complex. The structure shows that GpppG binds the RNA template through two Watson-Crick base pairs, with the primer 3'-hydroxyl oriented to attack the 5'-phosphate of the adjacent G residue. Thus, the GpppG structure suggests that the bound imidazolium-bridged dinucleotide intermediate would be preorganized to react with the primer by in-line SN2 substitution. The structures of bound GppG and GppppG suggest that the length and flexibility of the 5'-5' linkage are important for optimal preorganization of the complex, whereas the position of the 5'-phosphate of bound pGpG explains the slow rate of oligonucleotide ligation reactions. Our studies provide a structural interpretation for the observed reactivity of the imidazolium-bridged dinucleotide intermediate in nonenzymatic RNA primer extension. Insight into the mechanism of nonenzymatic RNA primer extension from the structure of an RNA-GpppG complex.,Zhang W, Tam CP, Walton T, Fahrenbach AC, Birrane G, Szostak JW Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7659-7664. doi:, 10.1073/pnas.1704006114. Epub 2017 Jul 3. PMID:28673998[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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