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Crystal structure of Botulinum neurotoxin serotype D ligand binding domain in complex with N-Acetylneuraminic acidCrystal structure of Botulinum neurotoxin serotype D ligand binding domain in complex with N-Acetylneuraminic acid
Structural highlights
Function[BXD_CLOBO] Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves the '60-Lys-|-Leu-61' bond of synaptobrevins-1 and -2. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe extraordinary high toxicity of botulinum neurotoxins primarily results from their specific binding and uptake into neurons. At motor neurons, the seven botulinum neurotoxin serotypes A-G (BoNT/A-G) inhibit acetylcholine release leading to flaccid paralysis. Uptake of BoNT/A, B, E, F and G requires a dual interaction with gangliosides and the synaptic vesicle proteins synaptotagmin or SV2, whereas little is known about the cell entry mechanisms of the serotypes C and D that display the lowest amino acid sequence identity compared to the other five serotypes. Here, we demonstrate that the neurotoxicity of BoNT/D depends on the presence of gangliosides by employing phrenic nerve hemidiaphragm preparations derived from mice expressing GM3, GM2, GM1 and GD1a or only GM3. High resolution crystal structures of the 50 kDa cell binding domain of BoNT/D alone and in complex with sialic acid as well as biological analyses of single site BoNT/D mutants identified two carbohydrate binding sites. One site is located at a position previously identified in BoNT/A, B, E, F and G but is lacking the conserved SXWY motif. The other site coordinating one molecule of sialic acid resembles the second ganglioside binding pocket of tetanus neurotoxin (TeNT), named the sialic acid pocket. Botulinum neurotoxin serotype D attacks neurons via two carbohydrate binding sites in a ganglioside dependent manner.,Strotmeier J, Lee K, Volker AK, Mahrhold S, Zong Y, Zeiser J, Zhou J, Pich A, Bigalke H, Binz T, Rummel A, Jin R Biochem J. 2010 Aug 12. PMID:20704566[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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