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Biological Chemistry

Enhancing Bioreceptor Responsiveness

Researchers use biomolecular design technique to rationally engineer cooperative receptors

by Stu Borman
October 13, 2014 | A version of this story appeared in Volume 92, Issue 41

A generalizable way of boosting bioreceptor sensitivity to small changes in ligand concentration could lead to improved biosensors and more responsive biomaterials (Proc. Natl. Acad. Sci. USA 2014, DOI: 10.1073/pnas.1410796111). The sensitivity of most protein or DNA biosensors is physically limited in that it usually takes a large change in ligand concentration before binding-site occupancy changes significantly. A two-order-of-magnitude concentration increase is typically required to boost binding-site occupancy of a receptor by one order of magnitude. To deal with this problem, nature uses multisite receptors with positive cooperativity—in which an initial ligand such as a drug molecule binds with lower affinity than subsequent ligand molecules, enhancing sensitivity to small changes in ligand concentration. Kevin W. Plaxco of the University of California, Santa Barbara, and coworkers have now designed DNA-based receptors that are similarly cooperative. Their two-site receptors unfold in the absence of a ligand. Binding a first ligand initiates folding, forming a second binding site that is easier to occupy. This sequence increases ligand affinity and improves receptor sensitivity to small concentration changes. Next steps include adapting this mechanism to proteins, Plaxco says.

A random squiggle organizes into a hairpin shape upon addition of a star. The shape then includes a star-shaped hole for a second star.
Credit: Courtesy of Kevin Plaxco
A designed DNA receptor is initially unfolded. Binding of a first ligand (star) initiates folding, creating a second binding site that is easier to occupy.


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