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LAG3外延结构揭示配体和抗体识别的功能界面
作者:小柯机器人 发布时间:2022/6/30 19:44:21

美国莫菲特癌症中心Vincent C. Luca团队通过LAG3外延结构揭示配体和抗体识别的功能界面。该项研究成果于2022年6月27日在线发表在《自然—免疫学》杂志上。

研究人员表示,免疫检查点受体淋巴细胞激活基因3蛋白(LAG3)与主要组织相容性复合体II类(MHC II类),或纤维蛋白原样蛋白1(FGL1)结合后抑制T细胞功能。尽管LAG3作为下一代免疫疗法的靶标出现,但人们几乎没有描述LAG3蛋白的分子结构或它如何与细胞配体结合的信息。

研究人员确定了人类和鼠类LAG3外延结构,揭示了由Ig结构域2介导的二聚体组装。表位图显示,一种有效的LAG3拮抗剂抗体通过与LAG3结构域1中灵活的"环2"区域结合,阻止了与MHC II和FGL1的相互作用。研究人员还通过将突变映射到LAG3和FGL1的结构上定义了LAG3-FGL1界面,并确定了FGL1交联会诱发高阶LAG3寡聚体的形成。这些见解可以指导基于LAG3的药物开发,并暗示配体介导的LAG3聚集是破坏T细胞激活的一种机制。

附:英文原文

Title: LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition

Author: Ming, Qianqian, Celias, Daiana P., Wu, Chao, Cole, Aidan R., Singh, Srishti, Mason, Charlotte, Dong, Shen, Tran, Timothy H., Amarasinghe, Gaya K., Ruffell, Brian, Luca, Vincent C.

Issue&Volume: 2022-06-27

Abstract: The immune checkpoint receptor lymphocyte activation gene 3 protein (LAG3) inhibits T cell function upon binding to major histocompatibility complex class II (MHC class II) or fibrinogen-like protein 1 (FGL1). Despite the emergence of LAG3 as a target for next-generation immunotherapies, we have little information describing the molecular structure of the LAG3 protein or how it engages cellular ligands. Here we determined the structures of human and murine LAG3 ectodomains, revealing a dimeric assembly mediated by Ig domain 2. Epitope mapping indicates that a potent LAG3 antagonist antibody blocks interactions with MHC class II and FGL1 by binding to a flexible ‘loop 2’ region in LAG3 domain 1. We also defined the LAG3–FGL1 interface by mapping mutations onto structures of LAG3 and FGL1 and established that FGL1 cross-linking induces the formation of higher-order LAG3 oligomers. These insights can guide LAG3-based drug development and implicate ligand-mediated LAG3 clustering as a mechanism for disrupting T cell activation.

DOI: 10.1038/s41590-022-01238-7

Source: https://www.nature.com/articles/s41590-022-01238-7

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex