Cholera is a diarrheal disease responsible for the deaths of thousands, possibly even hundreds of thousands of people every year, and its impact is predicted to further increase with climate change. It has been known for decades that
blood group O individuals suffer more severe symptoms of
cholera compared with individuals with other
blood groups (A, B and AB). The observed
blood group dependence is likely to be caused by the major
virulence factor of Vibrio cholerae, the
cholera toxin (CT). Here, we investigate the binding of
ABH blood group determinants to both classical and El Tor CTB-pentamers using saturation transfer difference NMR and show that all three
blood group determinants bind to both toxin variants. Although the details of the interactions differ, we see no large differences between the two toxin genotypes and observe very similar binding constants. We also show that the
blood group determinants bind to a site distinct from that of the primary receptor, GM1. Transferred NOESY data confirm that the conformations of the
blood group determinants in complex with both toxin variants are similar to those of reported X-ray and
solution structures. Taken together, this detailed analysis provides a framework for the interpretation of the epidemiological data linking the severity of
cholera infection and an individual's
blood group, and brings us one step closer to understanding the molecular basis of
cholera blood group dependence.