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1H, 13C, 15N chemical shift assignments of SHP2 SH2 domains in complex with PD-1 immune-tyrosine motifs.
Biomolecular NMR Assignments ( IF 0.8 ) Pub Date : 2020-04-01 , DOI: 10.1007/s12104-020-09941-y
Michelangelo Marasco 1 , John P Kirkpatrick 1, 2 , Teresa Carlomagno 1, 2
Affiliation  

Inhibition of immune checkpoint receptor Programmed Death-1 (PD-1) via monoclonal antibodies is an established anticancer immunotherapeutic approach. This treatment has been largely successful; however, its high cost demands equally effective, more affordable alternatives. To date, the development of drugs targeting downstream players in the PD-1-dependent signaling pathway has been hampered by our poor understanding of the molecular details of the intermolecular interactions involved in the pathway. Activation of PD-1 leads to phosphorylation of two signaling motifs located in its cytoplasmic domain, the immune tyrosine inhibitory motif (ITIM) and immune tyrosine switch motif (ITSM), which recruit and activate protein tyrosine phosphatase SHP2. This interaction is mediated by the two Src homology 2 (SH2) domains of SHP2, termed N-SH2 and C-SH2, which recognize phosphotyrosines pY223 and pY248 of ITIM and ITSM, respectively. SHP2 then propagates the inhibitory signal, ultimately leading to suppression of T cell functionality. In order to facilitate mechanistic structural studies of this signaling pathway, we report the resonance assignments of the complexes formed by the signaling motifs of PD-1 and the SH2 domains of SHP2.

中文翻译:

与 PD-1 免疫酪氨酸基序复合的 SHP2 SH2 结构域的 1H、13C、15N 化学位移分配。

通过单克隆抗体抑制免疫检查点受体程序性死亡 1 (PD-1) 是一种成熟的抗癌免疫治疗方法。这种治疗大体上是成功的;然而,其高成本需要同样有效、更实惠的替代品。迄今为止,我们对通路中涉及的分子间相互作用的分子细节了解不足,阻碍了针对 PD-1 依赖性信号通路下游参与者的药物开发。PD-1 的激活导致位于其细胞质域中的两个信号基序磷酸化,即免疫酪氨酸抑制基序 (ITIM) 和免疫酪氨酸开关基序 (ITSM),它们募集和激活蛋白酪氨酸磷酸酶 SHP2。这种相互作用由 SHP2 的两个 Src 同源 2 (SH2) 域介导,称为 N-SH2 和 C-SH2,分别识别 ITIM 和 ITSM 的磷酸酪氨酸 pY223 和 pY248。然后 SHP2 传播抑制信号,最终导致 T 细胞功能的抑制。为了促进对该信号通路的机械结构研究,我们报告了由 PD-1 的信号基序和 SHP2 的 SH2 结构域形成的复合物的共振分配。
更新日期:2020-04-01
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