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Title: Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex

Abstract

Botulinum neurotoxins (BoNTs) are highly poisonous substances that are also effective medicines. Accidental BoNT poisoning often occurs through ingestion of Clostridium botulinum-contaminated food. Here, we present the crystal structure of a BoNT in complex with a clostridial nontoxic nonhemagglutinin (NTNHA) protein at 2.7 angstroms. Biochemical and functional studies show that NTNHA provides large and multivalent binding interfaces to protect BoNT from gastrointestinal degradation. Moreover, the structure highlights key residues in BoNT that regulate complex assembly in a pH-dependent manner. Collectively, our findings define the molecular mechanisms by which NTNHA shields BoNT in the hostile gastrointestinal environment and releases it upon entry into the circulation. These results will assist in the design of small molecules for inhibiting oral BoNT intoxication and of delivery vehicles for oral administration of biologics.

Authors:
; ; ; ; ; ; ; ;  [1]
  1. Cornell
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGNNIHNIAID
OSTI Identifier:
1035706
Resource Type:
Journal Article
Journal Name:
Science
Additional Journal Information:
Journal Volume: 335; Journal Issue: 02, 2012; Journal ID: ISSN 0036-8075
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CLOSTRIDIUM; CRYSTAL STRUCTURE; DESIGN; DRUGS; FOOD; FUNCTIONALS; INGESTION; ORAL ADMINISTRATION; POISONING; PROTEINS; RESIDUES; SHIELDS

Citation Formats

Gu, Shenyan, Rumpel, Sophie, Zhou, Jie, Strotmeier, Jasmin, Bigalke, Hans, Perry, Kay, Shoemaker, Charles B, Rummel, Andreas, Jin, Rongsheng, Tufts), Hannover-MED), and Sanford-Burnham). Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex. United States: N. p., 2012. Web. doi:10.1126/science.1214270.
Gu, Shenyan, Rumpel, Sophie, Zhou, Jie, Strotmeier, Jasmin, Bigalke, Hans, Perry, Kay, Shoemaker, Charles B, Rummel, Andreas, Jin, Rongsheng, Tufts), Hannover-MED), & Sanford-Burnham). Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex. United States. doi:10.1126/science.1214270.
Gu, Shenyan, Rumpel, Sophie, Zhou, Jie, Strotmeier, Jasmin, Bigalke, Hans, Perry, Kay, Shoemaker, Charles B, Rummel, Andreas, Jin, Rongsheng, Tufts), Hannover-MED), and Sanford-Burnham). Wed . "Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex". United States. doi:10.1126/science.1214270.
@article{osti_1035706,
title = {Botulinum Neurotoxin Is Shielded by NTNHA in an Interlocked Complex},
author = {Gu, Shenyan and Rumpel, Sophie and Zhou, Jie and Strotmeier, Jasmin and Bigalke, Hans and Perry, Kay and Shoemaker, Charles B and Rummel, Andreas and Jin, Rongsheng and Tufts) and Hannover-MED) and Sanford-Burnham)},
abstractNote = {Botulinum neurotoxins (BoNTs) are highly poisonous substances that are also effective medicines. Accidental BoNT poisoning often occurs through ingestion of Clostridium botulinum-contaminated food. Here, we present the crystal structure of a BoNT in complex with a clostridial nontoxic nonhemagglutinin (NTNHA) protein at 2.7 angstroms. Biochemical and functional studies show that NTNHA provides large and multivalent binding interfaces to protect BoNT from gastrointestinal degradation. Moreover, the structure highlights key residues in BoNT that regulate complex assembly in a pH-dependent manner. Collectively, our findings define the molecular mechanisms by which NTNHA shields BoNT in the hostile gastrointestinal environment and releases it upon entry into the circulation. These results will assist in the design of small molecules for inhibiting oral BoNT intoxication and of delivery vehicles for oral administration of biologics.},
doi = {10.1126/science.1214270},
journal = {Science},
issn = {0036-8075},
number = 02, 2012,
volume = 335,
place = {United States},
year = {2012},
month = {3}
}