Margulies, D. H., Natarajan, K., Rossjohn, J. & McCluskey, J. in Paul’s Fundamental Immunology (eds. Flajnik, M. F., Singh, N. J. & Holland, S. M.) (Wolters Kluwer, 2023).
Blum, J. S., Wearsch, P. A. & Cresswell, P. Pathways of antigen processing. Annu. Rev. Immunol. 31, 443–473 (2013).
Bottino, C., Picant, V., Vivier, E. & Castriconi, R. Natural killer cells and engagers: powerful weapons against cancer. Immunol. Rev. 328, 412–421 (2024).
Brown, D., Trowsdale, J. & Allen, R. The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue Antigens 64, 215–225 (2004).
Malnati, M. S. et al. Peptide specificity in the recognition of MHC class I by natural killer cell clones. Science 267, 1016–1018 (1995).
Sim, M. J. W. et al. Innate receptors with high specificity for HLA class I-peptide complexes. Sci. Immunol. 8, eadh1781 (2023).
Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613 (1999).
Shiroishi, M. et al. Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proc. Natl. Acad. Sci. USA 103, 16412–16417 (2006).
Marrack, P., Scott-Browne, J. P., Dai, S., Gapin, L. & Kappler, J. W. Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu. Rev. Immunol. 26, 171–203 (2008).
Rossjohn, J. et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33, 169–200 (2015).
Panda, A. K. et al. Cutting edge: inhibition of the interaction of NK inhibitory receptors with MHC class I augments antiviral and antitumor immunity. J. Immunol. 205, 567–572 (2020).
Kohrt, H. E. et al. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 123, 678–686 (2014).
Panda, A. K. et al. Antibody-mediated inhibition of HLA/LILR interactions breaks innate immune tolerance and induces antitumor immunity. Cancer Immunol. Res. 13, 1938–1955 (2025).
Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).
Paul, S. & Lal, G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front. Immunol. 8, 1124 (2017).
Abel, A. M., Yang, C., Thakar, M. S. & Malarkannan, S. Natural killer cells: development, maturation, and clinical utilization. Front. Immunol. 9, 1869 (2018).
Boyington, J. C. & Sun, P. D. A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. Mol. Immunol. 38, 1007–1021 (2002).
Natarajan, K., Dimasi, N., Wang, J., Mariuzza, R. & Margulies, D. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu. Rev. Immunol. 20, 853–885 (2002).
Kärre, K. On the immunobiology of natural killer cells: studies of murine NK-cells and their interactions with T-cells and T-lymphomas, Diss., Stockholm (1981).
Karlhofer, F. M., Ribaudo, R. K. & Yokoyama, W. M. MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature 358, 66–70 (1992).
Tormo, J., Natarajan, K., Margulies, D. & Mariuzza, R. Crystal structure of a lectin-like natural killer cell receptor bound to its MHC class I ligand. Nature 402, 623–631 (1999).
Li, Y. & Mariuzza, R. A. Structural basis for recognition of cellular and viral ligands by NK cell receptors. Front. Immunol. 5, 123 (2014).
Myers, J. A. & Miller, J. S. Exploring the NK cell platform for cancer immunotherapy. Nat. Rev. Clin. Oncol. 18, 85–100 (2021).
Maiorino, L., Dassler-Plenker, J., Sun, L. & Egeblad, M. Innate immunity and cancer pathophysiology. Annu. Rev. Pathol. 17, 425–457 (2022).
Kyrysyuk, O. & Wucherpfennig, K. W. Designing cancer immunotherapies that engage T cells and NK cells. Annu. Rev. Immunol. 41, 17–38 (2023).
Fenis, A., Demaria, O., Gauthier, L., Vivier, E. & Narni-Mancinelli, E. New immune cell engagers for cancer immunotherapy. Nat. Rev. Immunol. 24, 471–486 (2024).
Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).
Lee, H. T. et al. Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab. Sci. Rep. 7, 5532 (2017).
Panda, A. K. et al. Antibody mediated inhibition of HLA/LILR interactions breaks innate immune tolerance and induces antitumor immunity. Cancer Immunol. Res. 13, 1938–1955 (2025).
Pymm, P. et al. The structural basis for recognition of human leukocyte antigen class I molecules by the pan-HLA antibody W6/32. J. Immunol. 213, 876–885 (2024).
Rebai, N. & Malissen, B. Structural and genetic analyses of HLA class I molecules using monoclonal xenoantibodies. Tissue Antigens 22, 107–117 (1983).
Apps, R. et al. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology 127, 26–39 (2009).
Stewart, C. A. et al. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc. Natl. Acad. Sci. USA 102, 13224–13229 (2005).
van der Ploeg, K. et al. Modulation of human leukocyte antigen-C by human cytomegalovirus stimulates KIR2DS1 recognition by natural killer cells. Front. Immunol. 8, 298 (2017).
Henderson, R. & Hasnain, S. ‘Cryo-EM’: electron cryomicroscopy, cryo electron microscopy or something else? IUCrJ 10, 519–520 (2023).
Wu, M. & Lander, G. C. How low can we go? Structure determination of small biological complexes using single-particle cryo-EM. Curr. Opin. Struct. Biol. 64, 9–16 (2020).
Yip, K. M., Fischer, N., Paknia, E., Chari, A. & Stark, H. Atomic-resolution protein structure determination by cryo-EM. Nature 587, 157–161 (2020).
Han, Y. et al. High-yield monolayer graphene grids for near-atomic resolution cryoelectron microscopy. Proc. Natl. Acad. Sci. USA 117, 1009–1014 (2020).
Wright, K. M. et al. Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen. Nat. Commun. 14, 5063 (2023).
Vivian, J. P. et al. Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B. Nature 479, 401–405 (2011).
Boyington, J. C., Motyka, S. A., Schuck, P., Brooks, A. G. & Sun, P. D. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–543 (2000).
Hilton, H. G. & Parham, P. Missing or altered self: human NK cell receptors that recognize HLA-C. Immunogenetics 69, 567–579 (2017).
Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).
Jiang, J. et al. SARS-CoV-2 antibodies recognize 23 distinct epitopic sites on the receptor binding domain. Commun. Biol. 6, 953 (2023).
Orr, C. M. et al. Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility. Sci. Immunol. 7, eabm3723 (2022).
Elliott, I. G. et al. Structure-guided disulfide engineering restricts antibody conformation to elicit TNFR agonism. Nat. Commun. 16, 3495 (2025).
Joyce, M. G. & Sun, P. D. The structural basis of ligand recognition by natural killer cell receptors. J. Biomed. Biotechnol. 2011, 203628 (2011).
Lorig-Roach, N., Harpell, N. M. & DuBois, R. M. Structural basis for the activity and specificity of the immune checkpoint inhibitor lirilumab. Sci. Rep. 14, 742 (2024).
Tian, J. et al. ILT2 and ILT4 drive myeloid suppression via both overlapping and distinct mechanisms. Cancer Immunol. Res. 12, 592–613 (2024).
Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 (2018).
van Montfoort, N. et al. NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell 175, 1744–1755.e15 (2018).
Mandel, I. et al. BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression. J. Immunother. Cancer 10, e004859 (2022).
Villa-Alvarez, M. et al. Ig-like transcript 2 (ILT2) blockade and lenalidomide restore NK cell function in chronic lymphocytic leukemia. Front. Immunol. 9, 2917 (2018).
He, K. et al. Homeostatic self-MHC-I recognition regulates anti-metastatic function of mature lung natural killer cells. Biochem. Biophys. Res. Commun. 738, 150906 (2024).
Harris, L. J. et al. The three-dimensional structure of an intact monoclonal antibody for canine lymphoma. Nature 360, 369–372 (1992).
Harris, L. J., Larson, S. B., Hasel, K. W. & McPherson, A. Refined structure of an intact IgG2a monoclonal antibody. Biochemistry 36, 1581–1597 (1997).
Saphire, E. O., Parren, P. W., Barbas, C. F. 3rd, Burton, D. R. & Wilson, I. A. Crystallization and preliminary structure determination of an intact human immunoglobulin, b12: an antibody that broadly neutralizes primary isolates of HIV-1. Acta Crystallogr. D. Biol. Crystallogr. 57, 168–171 (2001).
Scapin, G. et al. Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat. Struct. Mol. Biol. 22, 953–958 (2015).
Blech, M. et al. Structure of a therapeutic full-length anti-NPRA IgG4 antibody: dissecting conformational diversity. Biophys. J. 116, 1637–1649 (2019).
Silverton, E. W., Navia, M. A. & Davies, D. R. Three-dimensional structure of an intact human immunoglobulin. Proc. Natl. Acad. Sci. USA 74, 5140–5144 (1977).
Guddat, L. W., Herron, J. N. & Edmundson, A. B. Three-dimensional structure of a human immunoglobulin with a hinge deletion. Proc. Natl. Acad. Sci. USA 90, 4271–4275 (1993).
Li, Y. et al. Structural insights into immunoglobulin M. Science 367, 1014–1017 (2020).
Chen, Q., Menon, R. P., Masino, L., Tolar, P. & Rosenthal, P. B. Structural basis for Fc receptor recognition of immunoglobulin M. Nat. Struct. Mol. Biol. 30, 1033–1039 (2023).
Chen, Q., Menon, R., Calder, L. J., Tolar, P. & Rosenthal, P. B. Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer. Nat. Commun. 13, 6314 (2022).
Brunger, A. T. Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. Nature 355, 472–475 (1992).
Pintilie, G. et al. Measurement of atom resolvability in cryo-EM maps with Q-scores. Nat. Methods 17, 328–334 (2020).
Sok, C. L., Rossjohn, J. & Gully, B. S. The evolving portrait of gammadelta TCR recognition determinants. J. Immunol. 213, 543–552 (2024).
Roomp, K. & Domingues, F. S. Predicting interactions between T cell receptors and MHC-peptide complexes. Mol. Immunol. 48, 553–562 (2011).
Xie, N. et al. Neoantigens: promising targets for cancer therapy. Signal Transduct. Target Ther. 8, 9 (2023).
Sharma, P. et al. Immune checkpoint therapy-current perspectives and future directions. Cell 186, 1652–1669 (2023).
Patel, K. K., Tariveranmoshabad, M., Kadu, S., Shobaki, N. & June, C. From concept to cure: the evolution of CAR-T cell therapy. Mol. Ther. 33, 2123–2140 (2025).
Vivier, E. et al. Natural killer cell therapies. Nature 626, 727–736 (2024).
Carlsten, M. et al. Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma. Clin. Cancer Res. 22, 5211–5222 (2016).
Wang, Z. et al. Universal PCR amplification of mouse immunoglobulin gene variable regions: the design of degenerate primers and an assessment of the effect of DNA polymerase 3’ to 5’ exonuclease activity. J. Immunol. Methods 233, 167–177 (2000).
Lo, M. et al. Effector-attenuating substitutions that maintain antibody stability and reduce toxicity in mice. J. Biol. Chem. 292, 3900–3908 (2017).
Jiang, J. et al. Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation. Nat. Commun. 13, 5470 (2022).
Mastronarde, D. N. Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 152, 36–51 (2005).
Punjani, A., Zhang, H. & Fleet, D. J. Non-uniform refinement: adaptive regularization improves single-particle cryo-EM reconstruction. Nat. Methods 17, 1214–1221 (2020).
Punjani, A. & Fleet, D. J. 3DFlex: determining structure and motion of flexible proteins from cryo-EM. Nat. Methods 20, 860–870 (2023).
Kabsch, W. XDS. Acta Crystallogr. D Biol. Crystallogr. 66, 125–132 (2010).
McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).
Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).
Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).
PyMOLThe PyMOL Molecular Graphics System, Version 3.0 Schrödinger, LLC.
Meng, E. C. et al. UCSF ChimeraX: tools for structure building and analysis. Protein Sci. 32, e4792 (2023).
Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 75, 861–877 (2019).
Huang, J. & MacKerell, A. D. Jr. CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J. Comput. Chem. 34, 2135–2145 (2013).
Jo, S., Kim, T., Iyer, V. G. & Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 29, 1859–1865 (2008).
Jorgensen, W. L., Chandrasekhar, J., Buckner, J. K. & Madura, J. D. Computer simulations of organic reactions in solution. Ann. N. Y. Acad. Sci. 482, 198–209 (1986).
Phillips, J. C. et al. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005).
Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an N-log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).
Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–8, 27–8 (1996).
