Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins

Sandra Zakrzewska; Samantha A Nixon; Zhou Chen; Holly S Hajare; Elizabeth R Park; John V Mulcahy; Kandis M Arlinghaus; Eduard Neu; Kirill Konovalov; Davide Provasi; Tod A Leighfield; Marta Filizola; J Du Bois; Daniel L Minor Jr

doi:10.1038/s41467-025-58903-2

Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins

Nat Commun. 2025 Apr 24;16(1):3885. doi: 10.1038/s41467-025-58903-2.

Authors

Sandra Zakrzewska¹, Samantha A Nixon¹, Zhou Chen^{1

2}, Holly S Hajare³, Elizabeth R Park³, John V Mulcahy³, Kandis M Arlinghaus⁴, Eduard Neu⁵, Kirill Konovalov⁵, Davide Provasi⁵, Tod A Leighfield⁴, Marta Filizola⁵, J Du Bois³, Daniel L Minor Jr^{6

7

8

9

10

11}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
² Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁴ National Oceanic and Atmospheric Administration, National Centers for Coastal Ocean Science, Charleston, SC, USA.
⁵ Department of Pharmacological Sciences, Ichan School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Cardiovascular Research Institute, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁷ Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁸ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
⁹ California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
¹⁰ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA, USA. daniel.minor@ucsf.edu.
¹¹ Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. daniel.minor@ucsf.edu.

Abstract

Dinoflagellates and cyanobacteria produce saxitoxin (STX) and ~50 congeners that disrupt bioelectrical signals by blocking voltage-gated sodium channels (Na_Vs). Consuming seafood carrying these toxins causes paralytic shellfish poisoning (PSP). Although Na_Vs and anuran STX binding proteins (saxiphilins, Sxphs) use convergent STX binding modes, the structural basis for STX congener recognition is unknown. Here, we show that American bullfrog (Rana catesbeiana) RcSxph and High Himalaya frog (Nanorana parkeri) NpSxph sequester STX congeners using a 'lock and key' mode shared with STX. Importantly, functional studies demonstrate that Sxph 'toxin sponges' reverse Na_V block by multiple STX congeners and detect these toxins in a radioligand binding assay (RBA) used for environmental testing. Together, our study establishes how Sxphs sequester select neurotoxins and uncover STX congener-specific interactions distinct from Na_Vs. These findings expand understanding of toxin sponge action and provide a foundation for strategies to monitor and mitigate the harmful effects of STX congeners.

MeSH terms

Animals
Anura* / metabolism
Carrier Proteins* / chemistry
Carrier Proteins* / metabolism
Dinoflagellida / metabolism
Protein Binding
Rana catesbeiana / metabolism
Saxitoxin* / chemistry
Saxitoxin* / metabolism
Saxitoxin* / toxicity
Voltage-Gated Sodium Channels / metabolism

Substances

Saxitoxin
Voltage-Gated Sodium Channels
Carrier Proteins

Abstract

MeSH terms

Substances

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