An aptamer agonist of the insulin receptor acts as a positive or negative allosteric modulator, depending on its concentration

Protein function: subtle surprises from controlling molecules Studying how an aptamer, a short section of RNA or DNA, affects the interaction of insulin with its membrane receptor protein offers further insights into aptamers in general. Aptamers can bind with high specificity and affinity to many target molecules, and affect the activity of many proteins. Researchers in South Korea led by Sun Sik Bae at Pusan National University and Sung Ho Ryu at Pohang University of Science and Technology explored the interaction of the aptamer IR-A62 with the membrane protein that binds to and responds to insulin. Whether IR-A62 activated or inhibited insulin's interaction and effects depended on both the aptamer and insulin concentrations. While increasing understanding of the insulin receptor protein, investigating this subtly variable effect could more generally refine and expand the use of aptamers in medicine. Aptamers are widely used as binders that interact with targets with high affinity or as inhibitors of the function of target molecules. However, they have also been used to modulate target protein function, which they achieve by activating the target or stabilizing its conformation. Here, we report a unique aptamer modulator of the insulin receptor (IR), IR-A62. Alone, IR-A62 acts as a biased agonist that preferentially induces Y1150 monophosphorylation of IR. However, when administered alongside insulin, IR-A62 shows variable binding cooperativity depending on the ligand concentration. At low concentrations, IR-A62 acts as a positive allosteric modulator (PAM) agonist that enhances insulin binding, but at high concentrations, it acts as a negative allosteric modulator (NAM) agonist that competes with insulin for IR. Moreover, the concentration of insulin affects the binding of IR-A62 to IR. Finally, the subcutaneous administration of IR-A62 to diabetic mice reduces blood glucose levels with a longer-lasting effect than insulin administration. These findings imply that aptamers can elicit various responses from receptors beyond those of a simple agonist or inhibitor. We expect further studies of IR-A62 to help reveal the mechanism of IR activation and greatly expand the range of therapeutic applications of aptamers.

Automated summary

Researchers have discovered a unique aptamer modulator called IR-A62 that affects the interaction between insulin and its receptor protein. The action of IR-A62 depends on its concentration relative to insulin, with low concentrations enhancing insulin binding and high concentrations competing with insulin for the receptor. In addition, injecting IR-A62 can lower blood glucose levels in diabetic mice with a longer-lasting effect than insulin injection. These findings suggest that aptamers can elicit various responses from receptors, expanding the potential therapeutic applications of aptamers.