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Structural analysis of HER2-trastuzumab complex reveals receptor conformational adaptation

Santiago Vacca1, Marcos Gragera2, Alejandro Buschiazzo3,4

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

Science Advances
|July 25, 2025
PubMed

Insights

Trastuzumab binding stabilizes a new Human Epidermal Growth Factor Receptor-2 (HER2) conformation. This structural change may block HER2 interaction with HER3, impacting cancer signaling pathways and TZB

Area of Science:

  • Structural biology
  • Molecular oncology
  • Biochemistry

Background:

  • Human Epidermal Growth Factor Receptor-2 (HER2) is a receptor tyrosine kinase implicated in various cancers via overexpression and aberrant signaling.
  • Trastuzumab (TZB), a monoclonal antibody, is a key therapeutic for HER2-overexpressing cancers, often used with chemotherapy.
  • Previous structural insights into HER2 relied on analyzing individual domains, limiting understanding of the full receptor's dynamics.

Purpose of the Study:

  • To elucidate the near full-length Human Epidermal Growth Factor Receptor-2 (HER2) structure using single-particle cryo-electron microscopy (cryo-EM).
  • To identify novel conformations of HER2, particularly in response to Trastuzumab (TZB) binding.
  • To gain insights into the mechanism of action of Trastuzumab (TZB) and its impact on HER2-HER3 interactions.

Main Methods:

  • Purification of near full-length Human Epidermal Growth Factor Receptor-2 (HER2).
  • Single-particle cryo-electron microscopy (cryo-EM) analysis of HER2.
  • Structural comparison of HER2 in canonical and Trastuzumab (TZB)-bound states.

Main Results:

  • Identification of a previously unreported conformation of the HER2 extracellular domain stabilized by Trastuzumab (TZB) binding.
  • This TZB-induced conformation may impede the association of HER2 with HER3, a critical interaction for oncogenic signaling.
  • The study provides detailed structural insights into the conformational dynamics of HER2 and the therapeutic mechanism of TZB.

Conclusions:

  • Trastuzumab (TZB) binding induces significant conformational changes in Human Epidermal Growth Factor Receptor-2 (HER2).
  • The newly identified HER2 conformation may represent a key mechanism by which TZB exerts its therapeutic effect by disrupting oncogenic HER2-HER3 signaling.
  • These findings enhance our understanding of HER2 receptor dynamics and Trastuzumab (TZB) action, potentially informing future therapeutic strategies.

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