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TitleStructural analysis of HER2-trastuzumab complex reveals receptor conformational adaptation.
Journal, issue, pagesSci Adv, Vol. 11, Issue 30, Page eadu9945, Year 2025
Publish dateJul 25, 2025
AuthorsSantiago Vacca / Marcos Gragera / Alejandro Buschiazzo / David Herreros / James M Krieger / Santiago Bonn-Garcia / Roberto Melero / Carlos Os Sorzano / Jose M Carazo / Ohad Medalia / Andreas Plückthun /
PubMed AbstractHuman epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase, associated with a variety of malignant tumors, usually through overexpression, resulting in aberrant signaling. ...Human epidermal growth factor receptor-2 (HER2) is a receptor tyrosine kinase, associated with a variety of malignant tumors, usually through overexpression, resulting in aberrant signaling. Trastuzumab (TZB), one of the monoclonal antibodies (mAbs) used in combination with chemotherapy, has become a major therapeutic for HER2-overexpressing cancers. Current structural understanding of HER2 and its interactions with other receptors and with different affinity agents has relied on numerous structures of individual domains of HER2. Here, we subjected purified near full-length HER2 to single-particle cryo-electron microscopy (cryo-EM) analysis. Besides the canonical conformation described in previous structural studies, we report a previously unreported conformation of the HER2 extracellular domain that is stabilized upon TZB binding, which might hamper association with HER3, a receptor with which HER2 forms an oncogenic unit. Together, our findings provide insights into the conformational dynamics of the HER2 receptor and the mechanism of action of TZB.
External linksSci Adv / PubMed:40712014 / PubMed Central
MethodsEM (single particle)
Resolution3.6 - 3.8 Å
Structure data

EMDB-52997, PDB-9qbf:
HER2/ErbB2 extracellular domain (ECD) in compact conformation in complex with trastuzumab (TZB) antibody
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-52998, PDB-9qbg:
HER2/ErbB2 extracellular domain (ECD) in extended conformation in complex with trastuzumab (TZB) antibody
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-52999, PDB-9qbh:
HER2/ErbB2 extracellular domain (ECD) from a near full-length construct solubilized in amphipols.
Method: EM (single particle) / Resolution: 3.77 Å

Source
  • homo sapiens (human)
  • aequorea victoria (jellyfish)
KeywordsSIGNALING PROTEIN / Receptor / tyrosine kinase / transmembrane / HER2

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