9O08

Structure of human MAIT A-F7 TCR in complex with human MR1-lumichrome

Summary for 9O08

• Entry DOI: 10.2210/pdb9o08/pdb
• Descriptor: Major histocompatibility complex class I-related gene protein, Beta-2-microglobulin, TCR-alpha, ... (8 entities in total)
• Functional Keywords: receptor, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 189080.50

Authors

Abdelaal, M.,Rossjohn, J.,Awad, W. (deposition date: 2025-04-02, release date: 2025-11-19, Last modification date: 2025-12-24)

Primary citation

Abdelaal, M.R.,Deng, J.,McInerney, M.P.,Ito, E.,Purcell, A.W.,Yamasaki, S.,Villadangos, J.A.,McWilliam, H.E.G.,Gherardin, N.A.,Rossjohn, J.,Awad, W.
The antigen-presenting molecule MR1 binds host-generated riboflavin catabolites.
J.Exp.Med., 223:-, 2026

PubMed Abstract: MHC class I-related protein (MR1) presents vitamin B-based antigens (Ags) to mucosal-associated invariant T (MAIT) cells. While microbial riboflavin (RF) precursors are well-documented MR1 ligands, it is unclear whether host-generated RF catabolites influence MR1 immunity. Here, we report that RF catabolites, including 10-formylmethylflavin (FMF), lumichrome, lumiflavin, and alloxazine, bind to MR1 with moderate affinity, while RF itself binds weakly. In contrast to the MR1-upregulating microbial RF precursors, RF catabolites reduced the surface level of MR1 by inducing its retention in the endoplasmic reticulum and inhibiting exit. These RF catabolites weakly competed with vitamin B-based Ags for MR1 binding, thereby selectively inhibiting MAIT activation. The crystal structures of MR1 with RF, FMF, lumiflavin, and lumichrome show binding in the A'-pocket of MR1. Here, lumichrome formed a "flavin bond" covalent interaction with MR1-Lys43 differing from the typical Schiff base. Collectively, we identified three-ringed isoalloxazines that bind MR1 and reduce surface levels, suggesting a potential role in dampening MAIT cell immunity.

PubMed: 41295949
DOI: 10.1084/jem.20250711

Experimental method

X-RAY DIFFRACTION (2.2 Å)