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Tetanus toxin (TeNT) 1 and the botulinum toxins (BoNTs) are members of the family of clostridial neurotoxins, produced by Clostridium tetani and Clostridium botulinum, respectively. These protein toxins are structurally and functionally related, each being synthesized as a 150-kDa single polypeptide, which is processed to give a 50-kDa amino-terminal L chain, disulfide-bonded to a 100-kDa carboxyl-terminal H chain. These toxins cause paralysis by inhibiting release of neurotransmitter from presynaptic nerve terminals. The differences in clinical symptoms that tetanus and botulinum toxins exhibit are due to the distinct sites of action of the toxins. TeNT undergoes retrograde transport from the neuromuscular junction to the central nervous system and targets inhibitory neurons within the spinal cord causing a spastic paralysis. In contrast, BoNTs do not undergo retrograde transport and target peripheral sensory neurons resulting in flaccid paralysis.

Whooping cough (pertussis) is a highly contagious acute respiratory illness of humans caused by the Gram-negative bacterial pathogen Bordetella pertussis. The AT (autotransporter) BrkA (Bordetella serum-resistance killing protein A) is an important B. pertussis virulence factor that confers serum resistance and mediates adherence. In the present study, we have solved the crystal structure of the BrkA β-domain at 3 Å (1 Å=0.1 nm) resolution. Special features are a hairpin-like structure formed by the external loop L4, which is observed fortuitously sitting inside the pore of the crystallographic adjacent β-domain, and a previously undiscovered hydrophobic cavity formed by patches on loop L4 and β-strands S5 and S6. This adopts a ubiquitous structure characteristic of all AT β-domains. Mutagenesis studies have demonstrated that the hairpin-like structure and hydrophobic cavity are crucial for BrkA passenger domain (virulence effector) translocation. This structure helps in understanding the molecular mechanism of AT assembly and secretion and provides a potential target for anti-pertussis drug design.

Syntheses of Fmoc amino acids having zinc-binding groups were prepared and incorporated into substrate inhibitor H3K27 peptides using Fmoc/tBu solid-phase peptide synthesis (SPPS). Peptide 11, prepared using Fmoc-Asu(NHOtBu)-OH, is a potent inhibitor (IC50 = 390 nM) of the core NuRD corepressor complex (HDAC1–MTA1–RBBP4). The Fmoc amino acids have the potential to facilitate the rapid preparation of substrate peptidomimetic inhibitor (SPI) libraries in the search for selective HDAC inhibitors.

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