High resolution crystal structures of  Clostridium botulinum  neurotoxin A3 and A4 binding domains

Davies, Jonathan; Rees, Jay; Liu, Sai Man; Acharya, K. Ravi

doi:10.1016/j.jsb.2017.12.010

Cited by 14 publications

(31 citation statements)

References 14 publications

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“…The quality of the electron density map was very good throughout the structure, with only two small loop regions (residues 1222–1228 and 1267–1271) that were not observable. The overall fold of the protein is very similar to H C /A3 and other BoNT binding domain structures where the N‐terminal half contains a 14 β‐strand ‘jelly‐roll fold’ and the C‐terminal half folds into a ‘β‐trefoil’ with a β‐hairpin that contains the conserved GBS (H..SxWY..G) (Fig. A).…”

Section: Resultsmentioning

confidence: 56%

“…The LC domain is then translocated into the cytosol of neurons at the neuromuscular junction where it catalyses the cleavage of its target SNARE protein . Previously we had reported the crystal structure of H C /A3 at 1.6 Å resolution ; here, we report the structure of H C /A3 in complex with GD1a to 1.75 Å resolution and highlight the key structural changes that occur upon ganglioside binding.…”

mentioning

confidence: 82%

“…Crystals were kept at 100 K using a liquid nitrogen jet while a total of 7200 X‐ray diffraction images were collected at 0.1° oscillations with exposures of 0.02 s using the I04 protein crystallography beamline at Diamond Light Source (Didcot, UK). Data processing was carried out using DIALS , and the structure was solved by molecular replacement with PHASER using the structure of H C /A3 (PDB code: http://www.rcsb.org/pdb/search/structidSearch.do?structureId=6F0O) as the search model. The model was refined with REFMAC5 and manually fitted in coot as part of the CCP4 program suite .…”

Section: Methodsmentioning

confidence: 99%

“…A resolution [14]; here, we report the structure of H C /A3 in complex with GD1a to 1.75 A resolution and highlight the key structural changes that occur upon ganglioside binding.…”

mentioning

confidence: 91%

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Crystal structure of botulinum neurotoxin subtype A3 cell binding domain in complex with GD1a co‐receptor ganglioside

2020

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Botulinum neurotoxins (BoNTs) are one of the most toxic proteins known to humans. Their molecular structure is comprised of three essential domains—a cell binding domain (HC), translocation domain and catalytic domain (light chain) . The HC domain facilitates the highly specific binding of BoNTs to the neuronal membrane via a dual‐receptor complex involving a protein receptor and a ganglioside. Variation in activity/toxicity across subtypes of serotype A has been attributed to changes in protein and ganglioside interactions, and their implications are important in the design of novel BoNT‐based therapeutics. Here, we present the structure of BoNT/A3 cell binding domain (HC/A3) in complex with the ganglioside GD1a at 1.75 Å resolution. The structure revealed that six residues interact with the three outermost monosaccharides of GD1a through several key hydrogen bonding interactions. A detailed comparison of structures of HC/A3 with HC/A1 revealed subtle conformational differences at the ganglioside binding site upon carbohydrate binding.

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Section: Resultsmentioning

confidence: 56%

mentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

“…A resolution [14]; here, we report the structure of H C /A3 in complex with GD1a to 1.75 A resolution and highlight the key structural changes that occur upon ganglioside binding.…”

mentioning

confidence: 91%

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Crystal structure of botulinum neurotoxin subtype A3 cell binding domain in complex with GD1a co‐receptor ganglioside

2020

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“…Subtype differences of the Hc domains from BoNT/A3 and BoNT/A4 provide a plausible explanation of how the structural differences may play a role in receptor binding and the subsequent different symptoms observed. Indeed, the mutations evidenced on the BoNT/A3 and A4 binding domains explain their differential binding mode [ 69 ].…”

Section: Susceptibility To Different Botulinum Neurotoxin Toxinotymentioning

confidence: 99%

Variability of Botulinum Toxins: Challenges and Opportunities for the Future

Rasetti-Escargueil

Lemichez

Popoff

2018

Toxins

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Botulinum neurotoxins (BoNTs) are the most potent known toxins, and are therefore classified as extremely harmful biological weapons. However, BoNTs are therapeutic drugs that are widely used and have an increasing number of applications. BoNTs show a high diversity and are divided into multiple types and subtypes. Better understanding of the activity at the molecular and clinical levels of the natural BoNT variants as well as the development of BoNT-based chimeric molecules opens the door to novel medical applications such as silencing the sensory neurons at targeted areas and dermal restoration. This short review is focused on BoNTs’ variability and the opportunities or challenges posed for future clinical applications.

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High‐resolution crystal structures of the botulinum neurotoxin binding domains from subtypes A5 and A6

et al. 2020

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Botulinum neurotoxins (BoNTs) cause the deadly condition called botulism, but they can be used as therapeutics for a wide range of indications. BoNTs are classified into many different serotypes and subtypes, each with potentially different intoxication properties. Here, we report crystal structures of the receptor‐binding domains from two subtypes (BoNT/A5 and BoNT/A6) and compare their binding sites with previous BoNT/A structures.

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High resolution crystal structures of Clostridium botulinum neurotoxin A3 and A4 binding domains

Cited by 14 publications

References 14 publications

Crystal structure of botulinum neurotoxin subtype A3 cell binding domain in complex with GD1a co‐receptor ganglioside

Crystal structure of botulinum neurotoxin subtype A3 cell binding domain in complex with GD1a co‐receptor ganglioside

Variability of Botulinum Toxins: Challenges and Opportunities for the Future

High‐resolution crystal structures of the botulinum neurotoxin binding domains from subtypes A5 and A6

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