ABC toxins are secreted protein toxins produced by a wide range of Gram positive and Gram negative bacteria.  They are the predominant virulence factors in many insect pathogens, where they function as cytotoxins, targeting the actin cytoskeleton of gut epithelial cells in susceptible hosts, triggering apoptic cell death.  Genes encoding related toxins have been identified in human pathogens, although their role in virulence is currently unclear.  Moreover, it now appears that an analogous mechanism may be employed by eukaryotic cells for the generalised packaging and directed translocation of of bioactive peptides such as neuropeptides.  This has led to a heightened interest in the mechanism of virulence employed by ABC toxins, coinciding with recent breakthroughs in the understanding of their structure and molecular mechanism, that in turn have largely been enabled by recent technological breakthroughs in cryo-EM.

Despite only being discovered less than 15 years ago, the ABC toxin from Y. entomophaga (YenTc) has become a prototype of the ABC toxin family,  It was the first ABC toxin to have its full 3D structure determined¹ and remains the largest (2.3MDa) and most complex example (7 unique polypeptide chains arranged non-stochiometrically into a 22 subunit particle) of an ABC toxin characterised to date.  More recently, we determined the structure of the 220kDa BC subunit of the YenTc using X-ray crystallography.  This provided the first insights at atomic resolution into the mechanism that allows ABC toxins to in the first instance produce, store and translocate a potent cytotoxin, and subsequently release this toxin in response to specific, physiological stimuli.²  Here we will present new structural data that has allowed us to visualise at an average resolution of ~5Å the structure of the 2.1MDa YenTc A subunit.  This structure provides new insights into how the A subunit is responsible for determining host cell specificity and therefore opens up exciting possibilities for understanding differences in host susceptibility to ABC-toxin-producing pathogens, and potentially engineering new toxins for biotechnological applications.