globalchange  > 气候变化与战略
DOI: 10.1073/pnas.2003136117
论文题名:
Ligand-dependent downregulation of MR1 cell surface expression
作者: Salio M.; Awad W.; Veerapen N.; Gonzalez-Lopez C.; Kulicke C.; Waithe D.; Martens A.W.J.; Lewinsohn D.M.; Hobrath J.V.; Cox L.R.; Rossjohn J.; Besra G.S.; Cerundolo V.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2020
卷: 117, 期:19
起始页码: 10465
结束页码: 10475
语种: 英语
Scopus关键词: 3 [(2,6 dioxo 1,2,3,6 tetrahydropyrimidin 4 yl)formamido]propanoic acid ; 5 (2 oxopropylideneamino) 6 dextro ribitylaminouracil ; ligand ; methyl 3 [(2,6 dioxo 1,2,3,6 tetrahydropyrimidin 4 yl)formamido]propanoate ; propionic acid ; Schiff base ; T lymphocyte receptor ; unclassified drug ; uracil ; HLA antigen class 1 ; ligand ; lymphocyte antigen receptor ; minor histocompatibility antigen ; MR1 protein, human ; riboflavin ; antigen presentation ; Article ; binding affinity ; cell surface ; cell transport ; controlled study ; down regulation ; endoplasmic reticulum ; human ; human cell ; hydrophobicity ; ligand binding ; mucosal-associated invariant T cell ; priority journal ; T lymphocyte activation ; cell line ; cell membrane ; down regulation ; gene expression regulation ; genetics ; lymphocyte activation ; metabolism ; mucosal-associated invariant T cell ; protein transport ; THP-1 cell line ; Antigen Presentation ; Cell Line ; Cell Membrane ; Down-Regulation ; Gene Expression Regulation ; Histocompatibility Antigens Class I ; Humans ; Ligands ; Lymphocyte Activation ; Minor Histocompatibility Antigens ; Mucosal-Associated Invariant T Cells ; Protein Transport ; Receptors, Antigen, T-Cell, alpha-beta ; Riboflavin ; THP-1 Cells
英文摘要: 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. © 2020 National Academy of Sciences. All rights reserved.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163468
Appears in Collections:气候变化与战略

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作者单位: Salio, M., MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; Awad, W., Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Veerapen, N., Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom; Gonzalez-Lopez, C., MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; Kulicke, C., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, United States, Research Department, Portland Veterans Administration Healthcare System, Portland, OR 97239, United States; Waithe, D., MRC Centre for Computational Biology, Wolfson Imaging Centre, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; Martens, A.W.J., MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; Lewinsohn, D.M., Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, United States, Research Department, Portland Veterans Administration Healthcare System, Portland, OR 97239, United States; Hobrath, J.V., Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom; Cox, L.R., School of Chemistry, University of Birmingham, Birmingham, B15 2TT, United Kingdom; Rossjohn, J., Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia, Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom; Besra, G.S., Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom; Cerundolo, V., MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom

Recommended Citation:
Salio M.,Awad W.,Veerapen N.,et al. Ligand-dependent downregulation of MR1 cell surface expression[J]. Proceedings of the National Academy of Sciences of the United States of America,2020-01-01,117(19)
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