Structure of the Light Chain of Botulinum Neurotoxin Serotype A Bound to small Molecule InhibitorsStructure of the Light Chain of Botulinum Neurotoxin Serotype A Bound to small Molecule Inhibitors
Structural highlights
2g7n is a 1 chain structure with sequence from Clostridium botulinum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
BXA2_CLOBJ Botulinum toxin causes flaccid paralysis by inhibiting neurotransmitter (acetylcholine) release from the presynaptic membranes of nerve terminals of eukaryotic host skeletal and autonomic nervous system, with frequent heart or respiratory failure. Precursor of botulinum neurotoxin A2 which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins found in synaptic vesicles. Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them. Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway. When the pH of the toxin-containing endosome drops a structural rearrangement occurs so that the N-terminus of the HC forms pores that allows the light chain (LC) to translocate into the cytosol. Once in the cytosol the disulfide bond linking the 2 subunits is reduced and LC cleaves its target protein on synaptic vesicles, preventing their fusion with the cytoplasmic membrane and thus neurotransmitter release (By similarity).[UniProtKB:P0DPI0] Has proteolytic activity. After translocation into the eukaryotic host cytosol, LC hydrolyzes the 197-Gln-|-Arg-198 bond in SNAP25, blocking neurotransmitter release (PubMed:16846233).[1] Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into host cytosol. Composed of 3 subdomains; the translocation domain (TD), and N-terminus and C-terminus of the receptor-binding domain (RBD). The RBD is responsible for the adherence of the toxin to the cell surface. It simultaneously recognizes 2 coreceptors; polysialated gangliosides and the receptor protein SV2 in close proximity on host synaptic vesicles (PubMed:28252640, PubMed:29649119). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site; it may also prevent premature LC dissociation from the translocation channel and to protect toxin prior to translocation (By similarity). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (By similarity).[UniProtKB:P0DPI0][2][3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
↑Fu Z, Chen S, Baldwin MR, Boldt GE, Crawford A, Janda KD, Barbieri JT, Kim JJ. Light chain of botulinum neurotoxin serotype A: structural resolution of a catalytic intermediate. Biochemistry. 2006 Jul 25;45(29):8903-11. PMID:16846233 doi:10.1021/bi060786z
↑Benoit RM, Scharer MA, Wieser MM, Li X, Frey D, Kammerer RA. Crystal structure of the BoNT/A2 receptor-binding domain in complex with the luminal domain of its neuronal receptor SV2C. Sci Rep. 2017 Mar 2;7:43588. doi: 10.1038/srep43588. PMID:28252640 doi:http://dx.doi.org/10.1038/srep43588
↑Gustafsson R, Zhang S, Masuyer G, Dong M, Stenmark P. Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding. Toxins (Basel). 2018 Apr 12;10(4). pii: toxins10040153. doi:, 10.3390/toxins10040153. PMID:29649119 doi:http://dx.doi.org/10.3390/toxins10040153
