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 alpha1 and alpha2 domains of classical MHC molecules without a bound peptide. The lack of alpha3 and beta2m domains is compensated by replacing two hydrophobic patches at the underside of the class I MHC-like beta sheet floor with a group of hydrophilic and charged residues in ULBP3. NKG2D binds diagonally across the ULBP3 alpha 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.
Radaev
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Structural Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 12441 Parklawn Drive, Rockville, MD 20852, USA.
Rostro
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Brooks
A G
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Colonna
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Sun
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D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D058851:GPI-Linked Proteins; D006680:HLA Antigens / Q000737:chemistry; D015236:HLA-C Antigens / Q000737:chemistry; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D036341:Intercellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type; D008024:Ligands; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry; D011961:Receptors, Fc / Q000737:chemistry; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
D015703:Antigens, CD; D002352:Carrier Proteins; D058851:GPI-Linked Proteins; C103673:HFE protein, human; D006680:HLA Antigens; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D037181:Lectins, C-Type; D008024:Ligands; C099187:MHC class I-related chain A; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011993:Recombinant Fusion Proteins; C423229:ULBP3 protein, human; C100688:Fc receptor, neonatal