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. 2021 Jun 21;4:762. doi: 10.1038/s42003-021-02253-4

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Monovalent, monoparatopic DARPins (9.26 binding to extracellular subdomain I, vermillion; G3 binding to extracellular subdomain IV, yellow) and design of bipDARPin 6L1G (right), connecting 9.26 and G3 through a short linker. b Ligand-activated (e.g., by heregulin, mint) HER2:HER3 (sky blue, blue) heterodimers are able to stimulate proliferation and survival. c, d Bivalent intermolecular binding of bipDARPins may induce the formation of (c) inactive dimers or (d) oligomerization into daisy chains. In both cases, the kinase domains are separated and thus inactive. HRG heregulin, TM transmembrane helix, KD kinase domain.