Common binding site for disialyllactose and tri-peptide in C-fragment of tetanus neurotoxin |
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Authors: | Jayaraman Seetharaman Eswaramoorthy Subramaniam Kumaran Desigan Swaminathan Subramanyam |
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Institution: | Biology Department, Brookhaven National Laboratory, Upton, New York 11973, USA. |
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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. |
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Keywords: | tetanus neurotoxin GD3 ganglioside X‐ray crystallography β‐trefoil inhibitors |
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