Agonistic aptamer to the insulin receptor leads to biased signaling and functional selectivity through allosteric modulation

Na Oh Yunn, Ara Koh, Seungmin Han, Jong Hun Lim, Sehoon Park, Jiyoun Lee, Eui Kim, Sung Key Jang, Per Olof Berggren, Sung Ho Ryu

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Due to their high affinity and specificity, aptamers have been widely used as effective inhibitors in clinical applications. However, the ability to activate protein function through aptamer-protein interaction has not been well-elucidated. To investigate their potential as target-specific agonists, we used SELEX to generate aptamers to the insulin receptor (IR) and identified an agonistic aptamer named IR-A48 that specifically binds to IR, but not to IGF-1 receptor. Despite its capacity to stimulate IR autophosphorylation, similar to insulin, we found that IR-A48 not only binds to an allosteric site distinct from the insulin binding site, but also preferentially induces Y1150 phosphorylation in the IR kinase domain. Moreover, Y1150-biased phosphorylation induced by IR-A48 selectively activates specific signaling pathways downstream of IR. In contrast to insulin-mediated activation of IR, IR-A48 binding has little effect on theMAPK pathway and proliferation of cancer cells. Instead, AKT S473 phosphorylation is highly stimulated by IR-A48, resulting in increased glucose uptake both in vitro and in vivo. Here, we present IR-A48 as a biased agonist able to selectively induce the metabolic activity of IR through allosteric binding. Furthermore, our study also suggests that aptamers can be a promising tool for developing artificial biased agonists to targeted receptors.

Original languageEnglish (US)
Pages (from-to)7688-7701
Number of pages14
JournalNucleic acids research
Issue number16
StatePublished - Jul 16 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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