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

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.

Authors:
ORCiD logo [1]; ORCiD logo [1];  [2]; ORCiD logo [1]; ORCiD logo [3]
  1. Univ. of California, San Francisco, CA (United States)
  2. Univ. of California, San Francisco, CA (United States); Gilead Sciences, Foster City, CA (United States)
  3. Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1599801
Grant/Contract Number:  
[AC02-05CH11231; NIH-NHLBI R01-H6080050; NIH-NIGMS GM117263-01A1]
Resource Type:
Accepted Manuscript
Journal Name:
Science Advances
Additional Journal Information:
[ Journal Volume: 5; Journal Issue: 6]; Journal ID: ISSN 2375-2548
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Yen, Tien-Jui, Lolicato, Marco, Thomas-Tran, Rhiannon, Du Bois, J., and Minor, Daniel L. Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins. United States: N. p., 2019. Web. doi:10.1126/sciadv.aax2650.
Yen, Tien-Jui, Lolicato, Marco, Thomas-Tran, Rhiannon, Du Bois, J., & Minor, Daniel L. Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins. United States. doi:10.1126/sciadv.aax2650.
Yen, Tien-Jui, Lolicato, Marco, Thomas-Tran, Rhiannon, Du Bois, J., and Minor, Daniel L. Wed . "Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins". United States. doi:10.1126/sciadv.aax2650. https://www.osti.gov/servlets/purl/1599801.
@article{osti_1599801,
title = {Structure of the saxiphilin:saxitoxin (STX) complex reveals a convergent molecular recognition strategy for paralytic toxins},
author = {Yen, Tien-Jui and Lolicato, Marco and Thomas-Tran, Rhiannon and Du Bois, J. and Minor, Daniel L.},
abstractNote = {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.},
doi = {10.1126/sciadv.aax2650},
journal = {Science Advances},
number = [6],
volume = [5],
place = {United States},
year = {2019},
month = {6}
}

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