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CCeMMP Seminar Series – Dr. Raphael Trenker May 2022

Structures of the HER2-HER3-NRG1b receptor complex reveal a dynamic dimer interface induced

The Human Epidermal Growth Factor Receptor 3 (HER3) and its close homolog, the orphan receptor HER2, are single pass transmembrane receptor tyrosine kinases that form a pro-oncogenic signaling complex upon binding to the HER3 ligand neuregulin-1b (NRG1b). Until recently, there were no structural insights into the HER2/HER3 heterodimer owing to the difficulties in its reconstitution in vitro. We isolated near full-length HER2/HER3/NRG1b heterocomplex and obtained a 2.9 Å cryo-electron microscopy (cryo-EM) reconstruction of the extracellular domain module, which revealed a surprisingly dynamic dimerization interface. Based on additional structures of this heterocomplex in which HER2 harbors its most frequently observed oncogenic mutation, S310F, and of this complex bound to the therapeutic antibody trastuzumab, it will be discussed how oncogenic mutations and therapeutics appear to exploit the intrinsic dynamics of the HER2/HER3 heterodimer.

Dr. Raphael Trunker

Postdoctoral Fellow

Natalia Jura Lab

Cardiovascular Research Institute

University of California San Francisco