Structural Insights into the Inhibitory Mechanism of an Antibody against B7-H6, a Stress-Induced Cellular Ligand for the Natural Killer Cell Receptor NKp30

Xiaoping Xu, Emilie Narni-Mancinelli, Claudia Cantoni, Yili Li, Sophie Guia, Laurent Gauthier, Qianming Chen, Alessandro Moretta, Frédéric Vély, Edward Eisenstein, Sneha Rangarajan, Eric Vivier, Roy A. Mariuzza

Research output: Contribution to journalArticlepeer-review

Abstract

Antibodies have been shown to block signaling through cell surface receptors using several mechanisms. The two most common are binding to the ligand-binding site of the receptor and, conversely, binding to the receptor-binding site of the ligand. Here, we investigated the inhibitory mechanism of an antibody (17B1.3) against human B7-H6, a stress-induced cellular ligand for the natural killer (NK) cell receptor NKp30. Binding of this antibody to B7-H6, a transmembrane protein expressed on tumor and other stressed cells, but not on normal cells, prevents NK cell activation via NKp30. We determined the crystal structure of antibody 17B1.3 in complex with the ectodomain of B7-H6 to 2.5 Å resolution. Surprisingly, 17B1.3 binds to a site on B7-H6 that is completely distinct from the binding site for NKp30, such that 17B1.3 does not block the NKp30–B7-H6 interaction. We then asked whether 17B1.3 prevents signaling by binding to a putative site for B7-H6 dimerization. However, structure-based mutations designed to disrupt potential B7-H6 dimerization through this site did not diminish NKp30-mediated cell activation. We conclude that the bulky 17B1.3 antibody most likely acts by sterically interfering with close cell–cell contacts at the NK cell–target cell interface that are required for NK cell activation. A similar inhibitory mechanism may apply to other antibodies, including therapeutic antibodies that block signaling through cell surface receptors whose ligands are also cell surface proteins.

Original languageEnglish
Pages (from-to)4457-4466
Number of pages10
JournalJournal of Molecular Biology
Volume428
Issue number22
DOIs
Publication statusPublished - Nov 6 2016

Keywords

  • antibody
  • antibody–ligand complex
  • crystal structure
  • NK cell activation
  • NK cell receptor

ASJC Scopus subject areas

  • Molecular Biology

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