Conformational plasticity revealed by the cocrystal structure of NKG2D and its class i MHC-like ligand ULBP3

NKG2D is known to trigger the natural killer (NK) cell lysis of various tumor and virally infected cells. In the NKG2D/ULBP3 complex, the structure of ULBP3 resembles the α1 and α2 domains of classical MHC molecules without a bound peptide. The lack of α3 and β2m domains is compensated by replacing two hydrophobic patches at the underside of the class I MHC-like β sheet floor with a group of hydrophilic and charged residues in ULBP3. NKG2D binds diagonally across the ULBP3 α helices, creating a complementary interface, an asymmetrical subunit orientation, and local conformational adjustments in the receptor. The interface is stabilized primarily by hydrogen bonds and hydrophobic interactions. Unlike the KIR receptors that recognize a conserved HLA region by a lock-and-key mechanism, NKG2D recognizes diverse ligands by an induced-fit mechanism.