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Activation of the proapoptotic death receptor DR5 by oligomeric peptide and antibody agonists

Bing Li1, Stephen J Russell, Deanne M Compaan

  • 1Department of Protein Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Journal of Molecular Biology
|July 25, 2006
PubMed

Insights

Researchers identified a key tripeptide motif in DR5-binding peptides and antibodies. This motif is crucial for recognizing the death receptor DR5 and shows potential for cancer therapy by inducing apoptosis.

Area of Science:

  • Molecular Biology
  • Immunology
  • Oncology

Background:

  • The cell-extrinsic apoptotic pathway is vital for development and homeostasis.
  • Targeting this pathway in cancer cells offers therapeutic potential.
  • DR5 is a key cell-surface death receptor involved in apoptosis.

Purpose of the Study:

  • To identify novel ligands that bind to the human death receptor DR5.
  • To characterize the molecular basis of DR5-ligand interactions.
  • To explore the therapeutic potential of DR5-targeting agents.

Main Methods:

  • Phage display technology was employed to discover DR5-binding peptides and antibodies.
  • X-ray crystallography was used to determine the structural basis of DR5-ligand binding.
  • Functional assays were performed to assess the proapoptotic activity of identified ligands.

Main Results:

  • A conserved tripeptide motif was identified in both DR5-binding peptides and antibodies.
  • This motif was found to be critical for DR5 recognition, located at the interface core.
  • Selected peptides and antibodies demonstrated potent proapoptotic activity in DR5-expressing lung cancer cells.

Conclusions:

  • The identified tripeptide motif is central to DR5 antigen recognition.
  • Phage-derived ligands targeting DR5 hold promise for cancer therapy.
  • These ligands can aid in understanding DR5 activation and developing synthetic agonists.

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