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HER2 与由色氨酸和丝氨酸侧链形成的抗体结合位形成的复合物结构。

Structure of the complex between HER2 and an antibody paratope formed by side chains from tryptophan and serine.

机构信息

Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

出版信息

J Mol Biol. 2010 Sep 10;402(1):217-29. doi: 10.1016/j.jmb.2010.07.027. Epub 2010 Jul 21.

Abstract

Engineered antibody paratopes with limited sequence diversity permit assessment of the roles played by different amino acid side chains in creating the high-affinity, high-specificity interactions characteristic of antibodies. We describe a paratope raised against the human ErbB family member HER2, using a binary diversity tryptophan/serine library displayed on phage. Fab37 binds to the extracellular domain of HER2 with sub-nanomolar affinity. An X-ray structure at 3.2 A resolution reveals a contact paratope composed almost entirely of tryptophan and serine residues. Mutagenesis experiments reveal which of these side chains are more important for direct antigen interactions and which are more important for conformational flexibility. The crystal lattice contains an unprecedented trimeric arrangement of HER2 closely related to previously observed homodimers of the related epidermal growth factor receptor.

摘要

工程化抗体的互补决定区具有有限的序列多样性,可以评估不同氨基酸侧链在形成抗体高亲和力和高特异性相互作用中的作用。我们描述了一种针对人表皮生长因子受体家族成员 HER2 的抗体互补决定区,使用噬菌体展示的二元多样性色氨酸/丝氨酸文库产生。Fab37 以亚纳摩尔亲和力与 HER2 的细胞外结构域结合。分辨率为 3.2A 的 X 射线结构揭示了一个由几乎完全由色氨酸和丝氨酸残基组成的接触互补决定区。突变实验揭示了这些侧链中哪些对于直接抗原相互作用更为重要,哪些对于构象灵活性更为重要。晶格中包含了一个前所未有的 HER2 三聚体排列,与之前观察到的相关表皮生长因子受体的同源二聚体非常相似。

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