Format

Send to

Choose Destination
Sci Adv. 2019 Jun 19;5(6):eaax2650. doi: 10.1126/sciadv.aax2650. eCollection 2019 Jun.

Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins.

Author information

1
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
3
Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
4
California Institute for Quantitative Biomedical Research, San Francisco, CA 94158, USA.
5
Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

Abstract

Dinoflagelates and cyanobacteria produce saxitoxin (STX), a lethal bis-guanidinium neurotoxin causing paralytic shellfish poisoning. A number of metazoans have soluble STX-binding proteins that may prevent STX intoxication. However, their STX molecular recognition mechanisms remain unknown. Here, we present structures of saxiphilin (Sxph), a bullfrog high-affinity STX-binding protein, alone and bound to STX. The structures reveal a novel high-affinity STX-binding site built from a "proto-pocket" on a transferrin scaffold that also bears thyroglobulin domain protease inhibitor repeats. Comparison of Sxph and voltage-gated sodium channel STX-binding sites reveals a convergent toxin recognition strategy comprising a largely rigid binding site where acidic side chains and a cation-π interaction engage STX. These studies reveal molecular rules for STX recognition, outline how a toxin-binding site can be built on a naïve scaffold, and open a path to developing protein sensors for environmental STX monitoring and new biologics for STX intoxication mitigation.

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center