| Structural highlights
6g5g is a 3 chain structure with sequence from "bacillus_botulinus"_van_ermengem_1896 "bacillus botulinus" van ermengem 1896. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Gene: | botB ("Bacillus botulinus" van Ermengem 1896) |
| Activity: | Bontoxilysin, with EC number 3.4.24.69 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[SYT2_HUMAN] Presynaptic congenital myasthenic syndromes. The disease is caused by variants affecting the gene represented in this entry.
Function
[BXB_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 '76-Gln-|-Phe-77' bond of synaptobrevin-2. [SYT2_HUMAN] Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).[UniProtKB:P46097][1]
Publication Abstract from PubMed
Although botulinum neurotoxin serotype A (BoNT/A) products are common treatments for various disorders, there is only one commercial BoNT/B product, whose low potency, likely stemming from low affinity toward its human receptor synaptotagmin 2 (hSyt2), has limited its therapeutic usefulness. We express and characterize two full-length recombinant BoNT/B1 proteins containing designed mutations E1191M/S1199Y (rBoNT/B1MY) and E1191Q/S1199W (rBoNT/B1QW) that enhance binding to hSyt2. In preclinical models including human-induced pluripotent stem cell neurons and a humanized transgenic mouse, this increased hSyt2 affinity results in high potency, comparable to that of BoNT/A. Last, we solve the cocrystal structure of rBoNT/B1MY in complex with peptides of hSyt2 and its homolog hSyt1. We demonstrate that neuronal surface receptor binding limits the clinical efficacy of unmodified BoNT/B and that modified BoNT/B proteins have promising clinical potential.
Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models.,Elliott M, Favre-Guilmard C, Liu SM, Maignel J, Masuyer G, Beard M, Boone C, Carre D, Kalinichev M, Lezmi S, Mir I, Nicoleau C, Palan S, Perier C, Raban E, Zhang S, Dong M, Stenmark P, Krupp J Sci Adv. 2019 Jan 16;5(1):eaau7196. doi: 10.1126/sciadv.aau7196. eCollection 2019, Jan. PMID:30746458[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yoo JC, Lim Ty, Park JS, Hah YS, Park N, Hong SG, Park JY, Yoon TJ. SYT14L, especially its C2 domain, is involved in regulating melanocyte differentiation. J Dermatol Sci. 2013 Dec;72(3):246-51. doi: 10.1016/j.jdermsci.2013.07.010. Epub , 2013 Aug 8. PMID:23999003 doi:http://dx.doi.org/10.1016/j.jdermsci.2013.07.010
- ↑ Elliott M, Favre-Guilmard C, Liu SM, Maignel J, Masuyer G, Beard M, Boone C, Carre D, Kalinichev M, Lezmi S, Mir I, Nicoleau C, Palan S, Perier C, Raban E, Zhang S, Dong M, Stenmark P, Krupp J. Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models. Sci Adv. 2019 Jan 16;5(1):eaau7196. doi: 10.1126/sciadv.aau7196. eCollection 2019, Jan. PMID:30746458 doi:http://dx.doi.org/10.1126/sciadv.aau7196
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