Holding onto the Edge: A New Look at How a SOMAmer Binds
A few fingers there, a couple more fingers over there and a couple well placed feet are all that separate rock climbers from the canyon floor hundreds of feet below. With the ease and grace of spiders, the experienced climbers maneuver quickly over the nearly smooth vertical rock face. What supernatural power do they have that keeps them from succumbing to gravity’s will? None. The climbers have instead developed the muscular strength, the know-how to maximize their grip and a few other handy tools to make the daunting feat easier.
SOMAmers are the elite rock climbers of the aptamer* world. They bear a set of “tools” that give them the advantage of gripping onto proteins in ways that other aptamers cannot. These tools include specialized chemical groups that provide the extra “sticky” factor necessary for SOMAmers to find new holds on their targeted proteins and latch on for an incredibly long period of time.
In recent years, a few papers have detailed how SOMAmers put these tools to work. A new discovery from Dr. Anna Marie Pyle’s lab at Yale University (in a collaboration with SomaLogic) has expanded our insight into how these super-aptamer rock climbers hold onto the rocky outcrops of proteins. They revealed the three-dimensional structure of a SOMAmer bound to interleukin 1α (IL-1α), a very difficult protein to bind with a traditional aptamer (Ren, Gelinas, von Carlowitz, Janjic, & Pyle, 2017). This detailed look at how the SOMAmer interacts with IL-1α revealed not only unique SOMAmer attributes, but also a view of IL-1α that had never been seen.
The structure of the IL-1α binder is truly unique, bearing little resemblance to anything that one might expect when told a SOMAmer is made from mostly DNA. The tiny SOMAmer looks like a ladder thrown off the side of a mountain and trampled by a herd of elephants. This contorted shape is thanks in part to the “tools” the SOMAmer possesses. Unlike other structures of SOMAmers in the literature, this one uses a fancy chemical attachment called “2Naphthyl” (Ren et al., 2017). In the structure, these 2Naphthyl tools form a building block (seen in other SOMAmer structures that use different “tools”) reminiscent of a miniature “zipper” that helps maintain the unusual bent shape (Ren et al., 2017). Aside from the little zipper, what’s really neat about this structure is its unexpectedness in this kind of molecule. It is a new take on “G-quadruplexes (Ren et al., 2017),” which are found throughout nature.
Given this unique and tortuous configuration, how does the SOMAmer hold onto its protein partner? Well, it turns out that the bent ladder structure created a “hand,” with the 2Naphthyl groups forming a sticky pocket in the palm of the hand that provided the bulk of the interaction’s strength (Ren et al., 2017). Additional contacts were made between negatively charged and positively charged atoms in the “fingers” (Ren et al., 2017).
As mentioned above, this unusual structure reveals a lot about the protein as well. Up until now, the research community was aware of the general structure of IL-1α, but knew none of the fine details (Ren et al., 2017). The inclusion of the SOMAmer hand in visualizing the structure helped pull the protein together to form an exquisite crystal that revealed the missing fine details. The research community now sees the elusive sidechains of IL-1α, which in turn illuminate the biology of inflammation and cancer development (Ren et al., 2017). As an extra bonus, the little SOMAmer could also inhibit the protein’s normal function; thus, making it a potential therapeutic for future development (Ren et al., 2017).
With a few tools and the ability to adopt contorted shapes, this tiny hand-like SOMAmer and others can tackle the most difficult of proteins and find great places to hold on. This sticky grip makes it possible to reach new vantage points not achievable by other types of technology. What can be seen from these lofty vantage points? Akin to the beautiful vistas bestowed to rock climbers, we will be able to gaze at never-before-seen vistas of our health.
*(a string of nucleic acids designed to bind to stuff)
Ren, X., Gelinas, A. D., von Carlowitz, I., Janjic, N., & Pyle, A. M. (2017). Structural basis for IL-1alpha recognition by a modified DNA aptamer that specifically inhibits IL-1alpha signaling. Nat Commun, 8(1), 810. doi:10.1038/s41467-017-00864-2