tailieunhanh - Báo cáo khoa học: Molecular structures and functional relationships in clostridial neurotoxins

The seven serotypes ofClostridium botulinumneurotoxins (A–G) are the deadliest poison known to humans. They share significant sequence homo-logy and hence possess similar structure–function relationships. Botulinum neurotoxins (BoNT) act via a four-step mechanism, viz., | IFEBS Journal REVIEW ARTICLE Molecular structures and functional relationships in clostridial neurotoxins Subramanyam Swaminathan Department of Biology Brookhaven NationalLaboratory Upton NY USA Keywords botulinum neurotoxin botulism catalytic activity drug discovery neuroexocytosis structure-function substrate-enzyme complex tetanus translocation X-ray crystallography zinc endopeptidase Correspondence S. Swaminathan Biology Department Brookhaven NationalLaboratory Upton NY 11973 USA Fax 1 631 344 3407 Tel 1 631 344 3187 E-mail swami@ Received 28 February 2011 revised 11 May 2011 accepted 17 May 2011 doi 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 .