Host-pathogen interactions are central to understanding microbial pathogenesis. 
The staphylococcal pore-forming cytotoxins hijack important immune molecules but 
little is known about the underlying molecular mechanisms of cytotoxin-receptor 
interaction and host specificity. Here we report the structures of a 
staphylococcal pore-forming cytotoxin, leukocidin GH (LukGH), in complex with 
its receptor (the α-I domain of complement receptor 3, CD11b-I), both for the 
human and murine homologs. We observe 2 binding interfaces, on the LukG and the 
LukH protomers, and show that human CD11b-I induces LukGH oligomerization in 
solution. LukGH binds murine CD11b-I weakly and is inactive toward murine 
neutrophils. Using a LukGH variant engineered to bind mouse CD11b-I, we 
demonstrate that cytolytic activity does not only require binding but also 
receptor-dependent oligomerization. Our studies provide an unprecedented insight 
into bicomponent leukocidin-host receptor interaction, enabling the development 
of antitoxin approaches and improved animal models to explore these approaches.