6PVD

Structure of human MAIT A-F7 TCR in complex with human MR1-NV18.1

Summary for 6PVD

• Entry DOI: 10.2210/pdb6pvd/pdb
• Descriptor: Major histocompatibility complex class I-related gene protein, Beta-2-microglobulin, Human TCR alpha chain, ... (9 entities in total)
• Functional Keywords: immune system, mait, mr1
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 188848.73

Authors

Awad, W.,Rossjohn, J. (deposition date: 2019-07-20, release date: 2020-04-01, Last modification date: 2024-11-06)

Primary citation

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.
Ligand-dependent downregulation of MR1 cell surface expression.
Proc.Natl.Acad.Sci.USA, 117:10465-10475, 2020

PubMed Abstract: 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.

PubMed: 32341160
DOI: 10.1073/pnas.2003136117

Experimental method

X-RAY DIFFRACTION (2.14 Å)