Structures of the active HER2/HER3 receptor complex reveal dynamics at the dimerization interface induced by binding of a single ligand
Structures of the active HER2/HER3 receptor complex reveal dynamics at the dimerization interface induced by binding of a single ligand
Abstract The Human Epidermal Growth Factor Receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β)1–3. The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. We isolated the NRG1β-bound near full-length HER2/HER3 dimer and obtained a 2.9? cryo-electron microscopy (cryo-EM) reconstruction of the extracellular domain module which reveals unexpected dynamics at the HER2/HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved likely because the apo HER2 monomer fails to undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm binding pocket. In a second structure of an oncogenic extracellular domain mutant of HER2, S310F, we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. We show that both HER2/HER3 and HER2-S310F/HER3 retain the capacity to bind to the HER2-directed therapeutic antibody, trastuzumab, but the mutant complex does not bind to pertuzumab. Our 3.5? structure of the HER2-S310F/HER3/NRG1β/trastuzumab Fragment antigen binding (Fab) complex shows that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, like oncogenic mutations, therapeutics exploit the intrinsic dynamics of the HER2/HER3 heterodimer. The unique features of a singly liganded HER2/HER3 heterodimer underscore the allosteric sensing of the ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via canonical active dimer interface.
Diwanji Devan、Trenker Raphael、Wang Feng、Agard David A.、Jura Natalia、Verba Kliment A.、Thaker Tarjani M.
Cardiovascular Research Institute, University of California San Francisco||Medical Scientist Training Program, University of California San FranciscoCardiovascular Research Institute, University of California San FranciscoDepartment of Biochemistry and Biophysics, University of California San FranciscoDepartment of Biochemistry and Biophysics, University of California San FranciscoCardiovascular Research Institute, University of California San Francisco||Department of Cellular and Molecular Pharmacology, University of California San FranciscoQuantitative Biosciences Institute (QBI), University of California San Francisco||Department of Pharmaceutical Chemistry, University of California San FranciscoCardiovascular Research Institute, University of California San Francisco||Department of Chemistry and Biochemistry, The University of Arizona
基础医学分子生物学肿瘤学
Diwanji Devan,Trenker Raphael,Wang Feng,Agard David A.,Jura Natalia,Verba Kliment A.,Thaker Tarjani M..Structures of the active HER2/HER3 receptor complex reveal dynamics at the dimerization interface induced by binding of a single ligand[EB/OL].(2025-03-28)[2025-07-09].https://www.biorxiv.org/content/10.1101/2021.05.03.442258.点此复制
评论