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Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5

Filip Radom1, Clemens Vonrhein2, Peer R E Mittl1

  • 1Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Acta Crystallographica. Section F, Structural Biology Communications
|July 1, 2021
PubMed

Insights

Researchers developed novel Designed Ankyrin-repeat Proteins (DARPins) targeting the human epidermal growth factor receptor 3 (HER3) extracellular domain. These DARPins show potential for developing new cancer therapeutics by inhibiting HER3 activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Structural Biology

Background:

  • The human epidermal growth factor receptor (HER) family, particularly HER3 (ErbB3), is crucial in cancer progression and tumor escape.
  • Designed Ankyrin-repeat Proteins (DARPins) are effective antibody mimetics used in clinical and research settings.
  • Previous DARPin development targeted EGFR, HER2, and HER4, with bivalent binders showing therapeutic promise.

Purpose of the Study:

  • To select and characterize DARPins that specifically target the extracellular domain 4 (HER3d4) of HER3.
  • To investigate the structural basis of DARPin-HER3 interaction for potential therapeutic applications.

Main Methods:

  • Selection of DARPins against HER3d4.
  • Crystallization of a selected DARPin (D5) in complex with HER3d4.
  • X-ray diffraction to determine the crystal structure at 2.3 and 2.0 Å resolution.

Main Results:

  • Successful selection of DARPins targeting HER3d4.
  • The crystal structure revealed that DARPin D5 binds to HER3d4 residues 568-577.
  • This epitope is involved in both inactive and active conformations of HER3, suggesting a mechanism for receptor modulation.

Conclusions:

  • DARPins targeting HER3 are a viable strategy for developing novel cancer therapeutics.
  • The structural insights into DARPin D5 binding provide a foundation for designing potent HER3-targeting drugs.
  • Targeting HER3 with DARPins could offer a new approach to combatting various cancers.
Keywords:
DARPinsEGFR familyHER3protein engineeringtumor targeting

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