气候变化领域集成服务门户(CCPortal): Ligand-dependent downregulation of MR1 cell surface expression

CCPortal

DOI	10.1073/pnas.2003136117
	Ligand-dependent downregulation of MR1 cell surface expression
	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.
发表日期	2020
ISSN	0027-8424
起始页码	10465
结束页码	10475
卷号	117 期号:19
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.
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
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/160293
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 Weathe...
推荐引用方式 GB/T 7714	Salio M.,Awad W.,Veerapen N.,et al. Ligand-dependent downregulation of MR1 cell surface expression[J],2020,117(19).
APA	Salio M..,Awad W..,Veerapen N..,Gonzalez-Lopez C..,Kulicke C..,...&Cerundolo V..(2020).Ligand-dependent downregulation of MR1 cell surface expression.Proceedings of the National Academy of Sciences of the United States of America,117(19).
MLA	Salio M.,et al."Ligand-dependent downregulation of MR1 cell surface expression".Proceedings of the National Academy of Sciences of the United States of America 117.19(2020).