1 H, 13 C, 15 N chemical shift assignments of SHP2 SH2 domains in complex with PD-1 immune-tyrosine motifs
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ARTICLE
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H, 13C, 15N chemical shift assignments of SHP2 SH2 domains in complex with PD‑1 immune‑tyrosine motifs Michelangelo Marasco1 · John P. Kirkpatrick1,2 · Teresa Carlomagno1,2 Received: 11 February 2020 / Accepted: 26 March 2020 © The Author(s) 2020
Abstract 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. Keywords PD-1 · SHP2 · Immunotherapy · SH2 domains
Biological context The recent success of anticancer therapies that target immune checkpoint receptor PD-1 has sparked considerable interest in the molecular details behind its signaling function. PD-1 is a 288-amino-acid receptor of the CD28 family, mostly expressed on the surface of T lymphocytes, whose main function is to maintain immune tolerance and prevent overactive T cell responses (Boussiotis 2016). However, PD-1 functionalities are also exploited by certain cancer types to evade immune surveillance; for this reason, monoclonal antibodies that block the interaction between this receptor and its activation ligand PD-L1 have proven successful in the treatment of tumors such as metastatic * Teresa Carlomagno [email protected]‑hannover.de 1
Center for Biomolecular Drug Design and Institute of Organic Chemistry, Leibniz University Hannover, Schneiderberg 38, 30167 Hannover, Germany
Helmholtz Center for Infection Research, Group of NMR-Based Structural Chemistry, Inhoffenstrasse 7, 38124 Braunschweig, Germany
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melanoma, non-small cell lung cancer and renal cell carcinoma (Page et al. 2014; Topalian et al. 2015). Despite their efficacy, the very high cost of immunotherapies poses a severe burden on public healthcare systems and calls for novel, equally effective, but more affordable drugs (Prasad et al. 2017). Targeting the PD-1-dependent signaling pathway has been made problematic by our limited knowledge of the molecular events following PD-1 activation; on
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