Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5,Acta Crystallographica Section F

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Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5
Acta Crystallographica Section F ( IF 1.1 ) Pub Date : 2021-06-29 , DOI: 10.1107/s2053230x21006002
Filip Radom ₁ , Clemens Vonrhein ₂ , Peer R E Mittl ₁ , Andreas Plückthun ₁

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The members of the human epidermal growth factor receptor (HER) family are among the most intensely studied oncological targets. HER3 (ErbB3), which had long been neglected, has emerged as a key oncogene, regulating the activity of other receptors and being involved in progression and tumor escape in multiple types of cancer. Designed ankyrin-repeat proteins (DARPins) serve as antibody mimetics that have proven to be useful in the clinic, in diagnostics and in research. DARPins have previously been selected against EGFR (HER1), HER2 and HER4. In particular, their combination into bivalent binders that separate or lock receptors in their inactive conformation has proved to be a promising strategy for the design of potent anticancer therapeutics. Here, the selection of DARPins targeting extracellular domain 4 of HER3 (HER3d4) is described. One of the selected DARPins, D5, in complex with HER3d4 crystallized in two closely related crystal forms that diffracted to 2.3 and 2.0 Å resolution, respectively. The DARPin D5 epitope comprises HER3d4 residues 568–577. These residues also contribute to interactions within the tethered (inactive) and extended (active) conformations of the extracellular domain of HER3.

中文翻译：

HER3胞外结构域4与设计的锚蛋白重复蛋白D5复合物的晶体结构

人类表皮生长因子受体 (HER) 家族的成员是研究最深入的肿瘤学靶标之一。长期以来被忽视的HER3（ErbB3）已成为一种关键的癌基因，调节其他受体的活性，并参与多种癌症的进展和肿瘤逃逸。设计的锚蛋白重复蛋白 (DARPins) 作为抗体模拟物，已被证明在临床、诊断和研究中有用。DARPins 之前已针对 EGFR (HER1)、HER2 和 HER4 选择。特别是，它们组合成二价结合剂，将受体分离或锁定在其非活性构象中，已被证明是设计有效抗癌疗法的有前途的策略。此处，描述了针对 HER3 (HER3d4) 胞外结构域 4 的 DARPins 的选择。选定的 DARPins 之一 D5 与 HER3d4 复合，以两种密切相关的晶体形式结晶，衍射分辨率分别为 2.3 和 2.0 Å。DARPin D5 表位包含 HER3d4 残基 568-577。这些残基还有助于 HER3 胞外结构域的束缚（非活性）和延伸（活性）构象内的相互作用。

更新日期：2021-07-01

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