Author interview: Basavraj Khanppnavar is a structural biologist and biochemist investigating membrane-associated cellular signaling complexes and their interactions with microbial toxins to advance their therapeutic and biotechnological applications.
Lab: Richard Kammerer and Volodymyr Korkhov, Paul Scherrer Institute / ETH Zürich
Research Summary: Our study reveals how Botulinum neurotoxins A1 (Botox) use the neuronal receptor SV2B and pH-dependent conformational changes to regulate entry into neurons, providing a blueprint for developing more effective Botox-based therapies.
What was the core problem you aimed to solve with this research?
Botulinum neurotoxins (BoNTs) produced by Clostridium botulinum and related species, are among the most potent toxins known to humans. While these toxins can cause botulism, a severe paralytic disease, however, their ability to selectively block neurotransmission has also made them powerful tools in biology and medicine.
BoNTs exist in multiple serotypes (BoNT/A to BoNT/G), each with distinct biological or therapeutic properties. BoNT/A1, and to some extent BoNT/B1, are used to treat neurological and non-neurological disorders including dystonia, migraines, and spasticity, as well as in cosmetic applications. One key factor influencing their medical use is onset of action. BoNT/A1 is preferred in both clinical and cosmetic applications for its slower onset and long-lasting effects, whereas BoNT/E, with a faster onset but shorter duration, is being explored for acute medical interventions.
Despite their medical significance, how these toxins control their translocation or enter the neuron remained poorly understood. Our study aimed to unravel this core problem at a molecular level, providing insights that could pave the way for tailored neurotoxin therapies with improved precision and enhanced botulism countermeasures.
How did you go about solving this problem?
We used cryo-electron microscopy (cryo-EM) to visualize the conformational states of Botulinum neurotoxin alone and bound to its receptor at physiologically relevant pH conditions at near-atomic resolution.
How would you explain your research outcomes (Key findings) to the non-scientific community?
Botox is one of the most powerful toxins known, yet in small, controlled doses, it is widely used in medicine to treat neurological disorders and in cosmetics to reduce wrinkles. Its effectiveness comes from its ability to precisely target nerve cells, but the details of how it enters these cells are still not fully understood.
Our research reveals how Botox attaches to specific receptors on nerve cells and changes shape to control when and how it enters cytosol. Understanding this process could help scientists and pharmaceutical companies develop safer and more effective Botox-based treatments for medical and cosmetic use.
In our study, we demonstrate for the first time the existence of large conformational changes in Botox and explain their purpose.
What are the potential implications of your findings for the field and society?
Our findings highlight the critical role of pH sensitivity and conformational dynamics in Botox’s ability to enter the interior of neurons. This study lays the foundation for further investigating the translocation mechanism of BoNTs and the molecular basis by which different serotypes such as BoNT/E exhibit distinct onset of action.
Together, these insights might inspire development of next-generation neurotoxin-based therapies by fixing certain conformations. With these developments, in future, researchers might be able to design tailored formulations with greater control over their effects, including some with longer-lasting effects for chronic conditions, others with faster action for acute interventions. This could further inspire broader applications in drug delivery and toxin-based therapeutics, leading to more effective and targeted medical treatments.
What was the exciting moment during your research?
One of the most exciting moments in our research was discovering how BoNT/A1 dynamically shifts conformations. Unbound, the neurotoxin remains highly flexible, adopting a semi-closed conformation. Surprisingly, upon binding SV2B, it stabilizes into an extended conformation incompatible with translocation. However, under acidic synaptic vesicle conditions, the toxin reverts to its semi-closed state, priming it for entry into the neuronal cytosol. This discovery, for the first time, reveals how Botox precisely controls the timing of its entry, with acidic conditions acting as a molecular switch to trigger translocation at the right moment.
Reference: Khanppnavar, B*., Leka, O*., Pal, S.K., Korkhov V.M, Kammerer R.A Cryo-EM structure of the botulinum neurotoxin A/SV2B complex and its implications for translocation. Nat Commun 16, 1224 (2025). https://doi.org/10.1038/s41467-025-56304-z * Equal contribution
📢 Calling All Indian Researchers! 📢
Are you an Indian researcher who has published a research article as the first author? Here’s an exciting opportunity to share your work with the public and get featured on the BioPatrika website! 🎙️✨
🔬 Why Participate?
✅ Showcase your research to a wider audience
✅ Gain visibility in the scientific community
✅ Contribute to science communication
📩 How to Apply?
Simply reach out to us at interview.biopatrika@gmail.com to share your research story!
🚀 Let’s make science accessible and inspire future innovators!
#BioPatrika #ScienceCommunication #IndianResearchers #ResearchHighlights #STEM
