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Ligand-dependent downregulation of MR1 cell surface expression

Salio, Mariolina, Awad, Wael, Veerapen, Natacha, Gonzalez-Lopez, Claudia, Kulicke, Corinna, Waithe, Dominic, Martens, Anne W. J., Lewinsohn, David M., Hobrath, Judith V., Cox, Liam R., Rossjohn, Jamie, Besra, Gurdyal S. and Cerundolo, Vincenzo 2020. Ligand-dependent downregulation of MR1 cell surface expression. Proceedings of the National Academy of Sciences 117 (19) , pp. 10465-10475. 10.1073/pnas.2003136117

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The antigen-presenting molecule MR1 presents riboflavin-based metabolites to Mucosal-Associated Invariant T (MAIT) cells. While MR1 egress to the cell surface is ligand-dependent, the ability of small-molecule ligands to impact on MR1 cellular trafficking remains unknown. Arising from an in silico screen of the MR1 ligand-binding pocket, we identify one ligand, 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoic acid, DB28, as well as an analog, methyl 3-([2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]formamido)propanoate, NV18.1, that down-regulate MR1 from the cell surface and retain MR1 molecules in the endoplasmic reticulum (ER) in an immature form. DB28 and NV18.1 compete with the known MR1 ligands, 5-OP-RU and acetyl-6-FP, for MR1 binding and inhibit MR1-dependent MAIT cell activation. Crystal structures of the MAIT T cell receptor (TCR) complexed with MR1-DB28 and MR1-NV18.1, show that these two ligands reside within the A′-pocket of MR1. Neither ligand forms a Schiff base with MR1 molecules; both are nevertheless sequestered by a network of hydrophobic and polar contacts. Accordingly, we define a class of compounds that inhibits MR1 cellular trafficking.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 17 September 2020
Date of Acceptance: 9 March 2020
Last Modified: 18 Sep 2020 13:30

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