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From Proteopedia
Structure of Ig-like V-type domian of mouse Programmed cell death 1 ligand 1 (PD-L1)
Structural highlights
FunctionPD1L1_MOUSE Plays a critical role in induction and maintenance of immune tolerance to self (PubMed:11238124). As a ligand for the inhibitory receptor PDCD1/PD-1, modulates the activation threshold of T-cells and limits T-cell effector response (PubMed:11238124). Through a yet unknown activating receptor, may costimulate T-cell subsets that predominantly produce interleukin-10 (IL10) (PubMed:11015443, PubMed:12719480).[1] [2] [3] The PDCD1-mediated inhibitory pathway is exploited by tumors to attenuate anti-tumor immunity and escape destruction by the immune system, thereby facilitating tumor survival (PubMed:12218188, PubMed:27281199). The interaction with PDCD1/PD-1 inhibits cytotoxic T lymphocytes (CTLs) effector function (PubMed:12218188). The blockage of the PDCD1-mediated pathway results in the reversal of the exhausted T-cell phenotype and the normalization of the anti-tumor response, providing a rationale for cancer immunotherapy (PubMed:12218188).[4] [5] Publication Abstract from PubMedIn the development of PD-L1-blocking therapeutics, it is essential to transfer initial in vitro findings into proper in vivo animal models. Classical immunocompetent mice are attractive due to high accessibility and low experimental costs. However, it is unknown whether inter-species differences in PD-L1 sequence and structure would allow for human-mouse cross applications. Here, we disclose the first structure of the mouse (m) PD-L1 and analyze its similarity to the human (h) PD-L1. We show that mPD-L1 interacts with hPD-1 and provides a negative signal toward activated Jurkat T cells. We also show major differences in druggability between the hPD-L1 and mPD-L1 using therapeutic antibodies, a macrocyclic peptide, and small molecules. Our study indicates that while the amino acid sequence is well conserved between the hPD-L1 and mPD-L1 and overall structures are almost identical, crucial differences determine the interaction with anti-PD-L1 agents, that cannot be easily predicted in silico. Human and mouse PD-L1: similar molecular structure, but different druggability profiles.,Magiera-Mularz K, Kocik J, Musielak B, Plewka J, Sala D, Machula M, Grudnik P, Hajduk M, Czepiel M, Siedlar M, Holak TA, Skalniak L iScience. 2020 Dec 24;24(1):101960. doi: 10.1016/j.isci.2020.101960. eCollection , 2021 Jan 22. PMID:33437940[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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