title: Common binding site for disialyllactose and tri-peptide in C-fragment of tetanus neurotoxin.
abstract: Clostridial neurotoxins are comprised of botulinum (BoNT) and tetanus (TeNT), which share significant structural and functional similarity. Crystal structures of the binding domain of TeNT complexed with disialyllactose (DiSia) and a tri-peptide Tyr-Glu-Trp (YEW) have been determined to 2.3 and 2.2 A, respectively. Both DiSia and YEW bind in a shallow cleft region on the surface of the molecule in the beta-trefoil domain, interacting with a set of common residues, Asp1147, Asp1214, Asn1216, and Arg1226. DiSia and YEW binding at the same site in tetanus toxin provides a putative site that could be occupied either by a ganglioside moiety or a peptide. Soaking experiments with a mixture of YEW and DiSia show that YEW competes with DiSia, suggesting that YEW can be used to block ganglioside binding. A comparison with the TeNT binding domain in complex with small molecules, BoNT/A and /B, provides insight into the different modes of ganglioside binding.
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Jayaraman
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Eswaramoorthy
authors.forename: Desigan
authors.initials: D
authors.lastname: Kumaran
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001905:Botulinum Toxins / Q000737:chemistry; D019274:Botulinum Toxins, Type A / Q000737:chemistry; D018360:Crystallography, X-Ray; D005732:Gangliosides / Q000737:chemistry; D008666:Metalloendopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013744:Tetanus Toxin / Q000737:chemistry*; D014312:Trisaccharides / Q000737:chemistry*
chemical_list: D005732:Gangliosides; D009842:Oligopeptides; D013744:Tetanus Toxin; D014312:Trisaccharides; C509062:disialyllactose; C509063:tyrosyl-glutamyl-tryptophan; C096323:rimabotulinumtoxinB; C035979:tetanospasmin; C016481:trisialoganglioside GT1; D008666:Metalloendopeptidases; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A