Activating and inhibitory receptors on natural killer (NK) cells have a crucial role in innate immunity. The activating receptor Ly49H confers resistance to infection with murine cytomegalovirus by binding to the 'immunoevasin' m157. We found that m157 bound to the helical stalk of Ly49H, whereby two m157 monomers engaged the Ly49H dimer. The helical stalks of Ly49H lay centrally across the m157 platform, whereas its lectin domain was not required for recognition. Instead, m157 targeted an 'aromatic peg motif' present in stalks of both activating and inhibitory receptors of the Ly49 family. Herein we dissect the role of Ly49 conformation on m157 binding and assess the impact of targeted m157 mutations on NK cell activation.