Nectin and nectin-like (NECL) adhesion molecules are broadly overexpressed in a wide range of cancers. By binding to these adhesion molecules, the immunoreceptors DNAX accessory molecule-1 (DNAM-1), CD96 molecule (CD96), and T cell immunoreceptor with Ig and ITIM domains (TIGIT) play a crucial role in regulating the anticancer activities of immune effector cells. However, within this axis, it remains unclear how DNAM-1 recognizes its cognate ligands. Here, we determined the structure of human DNAM-1 in complex with nectin-like protein-5 (NECL-5) at 2.8 Å resolution. Unexpectedly, we found that the two extracellular domains (D1–D2) of DNAM-1 adopt an unconventional "collapsed" arrangement that is markedly distinct from those in other immunoglobulin-based immunoreceptors. The DNAM-1:NECL-5 interaction was underpinned by conserved lock-and-key motifs located within their respective D1 domains, but also included a distinct interface derived from DNAM-1 D2. Mutation of the signature DNAM-1 "key" motif within the D1 domain attenuated NECL-5 binding and natural killer cell–mediated cytotoxicity. Altogether, our results have implications for understanding the binding mode of an immune receptor family that is emerging as a viable candidate for cancer immunotherapy.
Deuss, F. A., Watson, G. M., Goodall, K. J., Leece, I., Chatterjee, S., Fu, Z., ... Berry, R. (2019). Structural basis for the recognition of nectin-like protein-5 by the human activating immune receptor, DNAM-1. Journal of Biological Chemistry, 294(33), 12534-12546. https://doi.org/10.1074/jbc.RA119.009261