8BP6

Structure of MHC-class I related molecule MR1 with bound M3Ade.

Summary for 8BP6

• Entry DOI: 10.2210/pdb8bp6/pdb
• Descriptor: Beta-2-microglobulin,Major histocompatibility complex class I-related gene protein, (1R,5S)-8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde (3 entities in total)
• Functional Keywords: major histocompatibility complex class i-related gene protein, antigen, immnun system, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 89203.51

Authors

Berloffa, G.,Jakob, R.P.,Maier, T. (deposition date: 2022-11-16, release date: 2023-11-29, Last modification date: 2025-02-05)

Primary citation

Chancellor, A.,Constantin, D.,Berloffa, G.,Yang, Q.,Nosi, V.,Loureiro, J.P.,Colombo, R.,Jakob, R.P.,Joss, D.,Pfeffer, M.,De Simone, G.,Morabito, A.,Schaefer, V.,Vacchini, A.,Brunelli, L.,Montagna, D.,Heim, M.,Zippelius, A.,Davoli, E.,Haussinger, D.,Maier, T.,Mori, L.,De Libero, G.
The carbonyl nucleobase adduct M 3 Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells.
Immunity, 2024

PubMed Abstract: The major histocompatibility complex (MHC) class I-related molecule MHC-class-I-related protein 1 (MR1) presents metabolites to distinct MR1-restricted T cell subsets, including mucosal-associated invariant T (MAIT) and MR1T cells. However, self-reactive MR1T cells and the nature of recognized antigens remain underexplored. Here, we report a cell endogenous carbonyl adduct of adenine (8-(9H-purin-6-yl)-2-oxa-8-azabicyclo[3.3.1]nona-3,6-diene-4,6-dicarbaldehyde [MAde]) sequestered in the A' pocket of MR1. MAde induced in vitro MR1-mediated stimulation of MR1T cell clones that bound MR1-MAde tetramers. MR1-MAde tetramers identified heterogeneous MR1-reactive T cells ex vivo in healthy donors, individuals with acute myeloid leukemia, and tumor-infiltrating lymphocytes from non-small cell lung adenocarcinoma and hepatocarcinoma. These cells displayed phenotypic, transcriptional, and functional diversity at distinct differentiation stages, indicating their adaptive nature. They were also polyclonal, with some preferential T cell receptor (TCRαβ) pair usage. Thus, MAde is an MR1-presented self-metabolite that enables stimulation and tracking of human-MR1T cells from blood and tissue, aiding our understanding of their roles in health and disease.

PubMed: 39701104
DOI: 10.1016/j.immuni.2024.11.019

Experimental method

X-RAY DIFFRACTION (2.8 Å)