Molecular Structures and Functional Relationships in Clostridial Neurotoxins

Journal Article · Thu Dec 01 04:00:00 EST 2011 · FEBS Journal

DOI:https://doi.org/10.1111/j.1742-4658.2011.08183.x· OSTI ID:1041594

Swaminathan, S

The seven serotypes of Clostridium botulinum neurotoxins (A-G) are the deadliest poison known to humans. They share significant sequence homology and hence possess similar structure-function relationships. Botulinum neurotoxins (BoNT) act via a four-step mechanism, viz., binding and internalization to neuronal cells, translocation of the catalytic domain into the cytosol and finally cleavage of one of the three soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) causing blockage of neurotransmitter release leading to flaccid paralysis. Crystal structures of three holotoxins, BoNT/A, B and E, are available to date. Although the individual domains are remarkably similar, their domain organization is different. These structures have helped in correlating the structural and functional domains. This has led to the determination of structures of individual domains and combinations of them. Crystal structures of catalytic domains of all serotypes and several binding domains are now available. The catalytic domains are zinc endopeptidases and share significant sequence and structural homology. The active site architecture and the catalytic mechanism are similar although the binding mode of individual substrates may be different, dictating substrate specificity and peptide cleavage selectivity. Crystal structures of catalytic domains with substrate peptides provide clues to specificity and selectivity unique to BoNTs. Crystal structures of the receptor domain in complex with ganglioside or the protein receptor have provided information about the binding of botulinum neurotoxin to the neuronal cell. An overview of the structure-function relationship correlating the 3D structures with biochemical and biophysical data and how they can be used for structure-based drug discovery is presented here.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: US DEPARTMENT OF DEFENSE
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041594
• Report Number(s): BNL--95396-2011-JA
• Journal Information: FEBS Journal, Journal Name: FEBS Journal Journal Issue: 23 Vol. 278; ISSN 1742-464X
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
CLEAVAGE
CLOSTRIDIUM BOTULINUM
CRYSTAL STRUCTURE
CRYSTALLOGRAPHY
GANGLIOSIDES
MOLECULAR STRUCTURE
PEPTIDES
PROTEINS
SPECIFICITY
STRUCTURE FUNCTIONS
SUBSTRATES
TETANUS
TOXINS
TRANSLOCATION
X-ray crystallography
ZINC
botulinum neurotoxin
botulism
catalytic activity
drug discovery
neuroexocytosis
structure-function
substrate-enzyme complex
tetanus
translocation
zinc endopeptidase