9CGR | pdb_00009cgr

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 
    0.216 (Depositor), 0.216 (DCC) 
  • R-Value Work: 
    0.173 (Depositor), 0.173 (DCC) 
  • R-Value Observed: 
    0.174 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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Literature

MR1 presents vitamin B6-related compounds for recognition by MR1-reactive T cells.

McInerney, M.P.Awad, W.Souter, M.N.T.Kang, Y.Wang, C.J.H.Chan Yew Poa, K.Abdelaal, M.R.Le, N.H.Shepherd, C.M.McNeice, C.Meehan, L.J.Nelson, A.G.Raynes, J.M.Mak, J.Y.W.McCluskey, J.Chen, Z.Ang, C.S.Fairlie, D.P.Le Nours, J.Illing, P.T.Rossjohn, J.Purcell, A.W.

(2024) Proc Natl Acad Sci U S A 121: e2414792121-e2414792121

  • DOI: https://doi.org/10.1073/pnas.2414792121
  • Primary Citation of Related Structures:  
    9CGR, 9CGS

  • PubMed Abstract: 

    The major histocompatibility complex class I related protein (MR1) presents microbially derived vitamin B2 precursors to mucosal-associated invariant T (MAIT) cells. MR1 can also present other metabolites to activate MR1-restricted T cells expressing more diverse T cell receptors (TCRs), some with anti-tumor reactivity. However, knowledge of the range of the antigen(s) that can activate diverse MR1-reactive T cells remains incomplete. Here, we identify pyridoxal (vitamin B6) as a naturally presented MR1 ligand using unbiased mass spectrometry analyses of MR1-bound metabolites. Pyridoxal, and the related compound, pyridoxal 5-phosphate bound to MR1 and enabled cell surface upregulation of wild type MR1*01 and MR1 expressing the Arg9His polymorphism associated with the MR1*04 allotype in a manner dependent on Lys43-mediated Schiff-base formation. Crystal structures of MR1*01 in complex with pyridoxal and pyridoxal 5-phosphate showed how these ligands were accommodated within the A-pocket of MR1. T cell lines transduced with the 7.G5 TCR, which has reported "pan-cancer" specificity, were specifically activated by pyridoxal presented by antigen-presenting cells expressing MR1*01 and MR1 allotypes bearing the less common Arg9His polymorphism. 7.G5 T cells also recognized, to a lesser extent, pyridoxal 5-phosphate and, importantly, recognition of both vitamers was blocked by an anti-MR1 antibody. 7.G5 TCR reactivity toward pyridoxal was enhanced when presented by the Arg9His polymorphism-bearing MR1 allotypes. Vitamin B6, and vitamers thereof, have been associated with various cancers, and here we describe a link between this ligand, MR1, and its allomorphs, and the pan-cancer 7.G5 TCR. This work identifies an MR1 ligand that can activate a diverse MR1-restricted TCR.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Biology and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Major histocompatibility complex class I-related gene protein
A, C
271Homo sapiensMutation(s): 0 
Gene Names: MR1
UniProt & NIH Common Fund Data Resources
Find proteins for Q95460 (Homo sapiens)
Explore Q95460 
Go to UniProtKB:  Q95460
PHAROS:  Q95460
GTEx:  ENSG00000153029 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ95460
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulin
B, F
100Homo sapiensMutation(s): 0 
Gene Names: B2MCDABP0092HDCMA22P
UniProt & NIH Common Fund Data Resources
Find proteins for P61769 (Homo sapiens)
Explore P61769 
Go to UniProtKB:  P61769
PHAROS:  P61769
GTEx:  ENSG00000166710 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61769
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
TCR TRAV1-2
D, G
204Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
TCR TRBV 6-1
E, H
246Homo sapiensMutation(s): 0 
Entity Groups  
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PXL (Subject of Investigation/LOI)
Query on PXL

Download Ideal Coordinates CCD File 
I [auth A],
O [auth C]
3-HYDROXY-5-(HYDROXYMETHYL)-2-METHYLISONICOTINALDEHYDE
C8 H9 N O3
RADKZDMFGJYCBB-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth G]
J [auth A]
M [auth A]
P [auth C]
Q [auth C]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACY
Query on ACY

Download Ideal Coordinates CCD File 
K [auth A],
L [auth A],
S [auth C],
T [auth C],
V [auth C]
ACETIC ACID
C2 H4 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
BA [auth H]CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
N [auth A],
W [auth C]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free:  0.216 (Depositor), 0.216 (DCC) 
  • R-Value Work:  0.173 (Depositor), 0.173 (DCC) 
  • R-Value Observed: 0.174 (Depositor) 
Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 216.075α = 90
b = 69.897β = 103.833
c = 142.444γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted PXLClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Australian Research Council (ARC)Australia--

Revision History  (Full details and data files)

  • Version 1.0: 2024-11-27
    Type: Initial release
  • Version 2.0: 2024-12-11
    Changes: Atomic model, Data collection, Database references