6O3O

Structure of human DNAM-1 (CD226) bound to nectin-like protein-5 (necl-5)

Summary for 6O3O

• Entry DOI: 10.2210/pdb6o3o/pdb
• Descriptor: CD226 antigen, Poliovirus receptor, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: immune receptor, immunoglobulin domain, adhesion molecule, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 130501.71

Authors

Deuss, F.A.,Watson, G.M.,Rossjohn, J.,Berry, R. (deposition date: 2019-02-27, release date: 2019-07-10, Last modification date: 2024-10-16)

Primary citation

Deuss, F.A.,Watson, G.M.,Goodall, K.J.,Leece, I.,Chatterjee, S.,Fu, Z.,Thaysen-Andersen, M.,Andrews, D.M.,Rossjohn, J.,Berry, R.
Structural basis for the recognition of nectin-like protein-5 by the human-activating immune receptor, DNAM-1.
J.Biol.Chem., 294:12534-12546, 2019

PubMed Abstract: 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.

PubMed: 31253644
DOI: 10.1074/jbc.RA119.009261

Experimental method

X-RAY DIFFRACTION (2.8 Å)