Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Global Phasing Ltd, Sheraton House, Castle Park, Cambridge CB3 0AX, United Kingdom.
Acta Crystallogr F Struct Biol Commun. 2021 Jul 1;77(Pt 7):192-201. doi: 10.1107/S2053230X21006002. Epub 2021 Jun 29.
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.
人类表皮生长因子受体（HER）家族成员是研究最多的肿瘤靶点之一。HER3（ErbB3）长期以来被忽视，现已成为关键的致癌基因，调节其他受体的活性，并参与多种类型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、诊断和研究中非常有用。DARPins 以前曾针对 EGFR（HER1）、HER2 和 HER4 进行过选择。特别是，将它们组合成双价结合物，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治疗药物的一种很有前途的策略。本文描述了针对 HER3 细胞外结构域 4（HER3d4）的 DARPins 的选择。所选择的 DARPins 之一 D5 与 HER3d4 形成复合物，分别在两种密切相关的晶体形式中结晶，分辨率分别为 2.3 和 2.0 Å。DARPin D5 的表位包含 HER3d4 残基 568-577。这些残基也有助于 HER3 细胞外结构域的连接（无活性）和扩展（活性）构象内的相互作用。
