Sandbox Reserved 966: Difference between revisions

<StructureSection load='3BON' size='340' side='right' caption='BoNT/A-LC' scene='60/604485/General_introduction/2'>

The Clostridium botulinum neurotoxin produced by the bacteria ''Clostridium botulinum'' (and some strains of ''Clostridium butyricium'' and ''Clostridium baratii'') is the most lethal toxin known today. Seven serotypically botulinum neurotoxins (BoNTs) have been found, each of them is categorized into subtypes depending on their amino acid sequence. The protein is initially synthesized as a single polypeptide chain of ≈150 kDa and is then cleaved by a protease to yield the mature toxin, which consists of a light chain (LC which is 50 kDa) and a heavy chain (HC which is 100 kDa). LC and HC are held together by a long peptide belt, non-covalent interactions and a single inter-chain disulphide bond <ref>PMID: 24975322</ref> (see '''Figure 2''')

The Ramachandran diagram (see '''Figure 1''') shows the distribution of the residues in the protein. Amino acids are globally in favored regions.

[[Image:ramachandran3BON.png|thumb|'''Figure 1 :''' Ramachandran diagram of C.botulinum neurotoxin serotype A light chain (made using Python by Rémi Pelletier)]]

The <scene name='60/604485/Secondary_structure/1'>Secondary structure</scene> of BoNT/A-LC<ref>http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=3BON&bionumber=1</ref>

 

*The polypeptide forms 11 α-helices (we can notice a kink formed by <scene name='60/604485/Thr101/1'>Thr101</scene>, who may interact with an H from the N of Gly104)

*We can also find tree 3-10 helices (<scene name='60/604485/H3/2'>H3</scene>, <scene name='60/604485/H13/1'>H13</scene>, <scene name='60/604485/H14/1'>H14</scene>) 

*There are several  <scene name='60/604485/Sheets/1'>β sheets </scene> that are anti parallel except <scene name='60/604485/Sheets_parrallel/1'>this one.</scene>

* An interesting structure is also a typical  <scene name='60/604485/Betaturn/1'>β-turn</scene> : indeed the chain makes a sharp reversal by 180° within 4 residues, moreover Cα from the ''i'' residue and the Cα from the ''i+3'' residue are separated by less than 7 angstroms.

 

 

=== Mechanism & Catalytic site ===

 

 

The enzymatic reaction is shown on '''Figure 3''' and takes place at the <scene name='60/604485/Catalytic_site/2'>catalytic site</scene>. As it is developed on the scheme, a lot of residues and molecules of water are involved.

In the late 1960s, Edward Schantz and a San Francisco ophthalmologist, Alan Scott, started to work on the use of the botulinum toxin in therapeutic process.

First, they tried to treat strabismus and in the late 1970s the neurotoxin was used in many therapeutic applications.<ref>http://rms.medhyg.ch/numero-200-page-870.htm</ref>

=== Hyperhidrosis and CHARGE syndrome ===

We can now treat excessive sweating with botulinum toxin <ref>http://rms.medhyg.ch/numero-200-page-870.htm</ref> thanks to its action on the receptors of the parasympathetic network. Excessive dribbling can be treated in the same way.

Non-lethal amount of botulinum toxin can be injected locally to paralyse targeted muscles and reduce wrinkles temporally<ref>http://rms.medhyg.ch/numero-200-page-870.htm</ref> (5 to 6 months).

This pathologic can be treated by the same methode. Every anomalous behaviour of muscle tissue can be fixed thanks to the paralyzing effect of the toxin. It is based on the relaxation ok the muscles.

BoNT/A is used against cervical dystonia. But it can become inefficient after a period of use.