Daniel L. Minor, Jr., Ph.D.
Cardiovascular Research Institute, Departments of Biochemistry & Biophysics, and Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158 USA
The ability to resist toxins is found throughout the natural world and arises from a variety of molecular mechanisms. Although the most well-known mechanisms involve mutations in the proteins that are targets of the specific toxin, such changes inevitably come with a tradeoff that compromises the natural function of the target. ‘Toxin sponge’ proteins are a class of soluble, high-affinity toxin binding proteins that provide a direct means to counteract the lethal effects of toxins and avoid such target‑site mutation tradeoffs. Our laboratory has been studying the leading example of such ‘toxin sponge’ proteins, Saxiphilins (Sxphs) from frogs and toads. These soluble, ~90‑120 kDa proteins are high affinity receptors for saxitoxin (STX) and its congeners, toxins produced by harmful algal blooms of dinoflagellates and cyanobacteria in marine and freshwater environments that include the only marine toxin classified as a chemical weapon (STX). By using a combination of structural studies, binding assays, and functional studies, we have outlined the fundamental principles by which Sxphs recognize STX and its congeners. Remarkably, key toxin recognition features are shared with the physiological target of STX, voltage‑gated sodium channels (NaVs). Because their toxin binding affinities match those of NaVs, we have shown that Sxphs are able reverse toxin effects on NaVs in both cellular and in vivo settings. These findings highlight the potential to harness this protein class as antidotes STX and other toxins. I plan to present our most recent findings on high resolution structures that outline the molecular principles by which Sxphs engage STX and a variety of STX congeners.