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PDBsum entry 3gmm
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Immune system
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PDB id
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3gmm
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References listed in PDB file
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Key reference
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Title
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Structural evaluation of potent nkt cell agonists: implications for design of novel stimulatory ligands.
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Authors
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A.Schiefner,
M.Fujio,
D.Wu,
C.H.Wong,
I.A.Wilson.
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Ref.
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J Mol Biol, 2009,
394,
71-82.
[DOI no: ]
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PubMed id
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Abstract
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Natural killer T (NKT) cells are a subset of T cells that are activated by
CD1d-glycolipid complexes through a semi-invariant alphabeta T cell receptor
(NKT TCR). Upon activation, NKT cells secrete regulatory cytokines that are
implicated in T helper cell responses. alpha-Galactosylceramide (alpha-GalCer)
is a potent NKT cell agonist when presented by CD1d. Phenyl ring substitutions
of the alpha-GalCer fatty acid moiety were recently found to be superior in
eliciting regulatory cytokines. Crystal structures of four new mouse CD1d-lipid
complexes (five structures), a new PBS-25 complex, and CD1d with an endogenous
ligand, at 1.6-1.9 A resolution, reveal that the alpha-GalCer phenyl analogues
impart minor structural differences to the A'-pocket, while the sphingosine and
galactose moieties, important for NKT TCR recognition, remain virtually
unchanged. The observed differences in cytokine-release profiles appear to be
associated with increased stability of the CD1d-glycolipid complexes rather than
increased affinity for the NKT TCR. Furthermore, comparison of mouse
CD1d-glycolipid complexes in different crystallographic space groups reveals
considerable conformational variation, particularly above the F'-pocket, the
primary site of interaction with the NKT TCR. We propose that modifications of
the sphingosine moiety or other substitutions that decrease alpha-GalCer
flexibility would stabilize the F'-pocket. Such compounds might then increase
CD1d affinity for the NKT TCR and further enhance the stimulatory and regulatory
properties of alpha-GalCer derivatives.
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Figure 1.
Fig. 1. Structural overview of mCD1d–glycolipid complexes.
A schematic representation of the mCD1d–C8PhF complex is shown
in side view (a) and top view (b) rotated by 90° around the
x-axis from (a). The CD1d heavy-chain α1–α3 is highlighted
in light blue, β2m in light green, glycosylation sites as gray
sticks with red oxygens, C8PhF ligand in yellow, and A′-lipid
(AL), which is acquired from the cells during expression, in
blue. (c) Schematic drawings of the ligands used in this study.
The template α-GalCer is shown in black for comparison. Ligands
PBS-25, C6Ph, C8Ph, C8PhF, and C10Ph are derivatives of
α-GalCer, in which the C[26] fatty acid is replaced by either a
shorter fatty acid or a short fatty acid that terminates with a
phenyl ring.
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Figure 4.
Fig. 4. Ligand contact analysis of mCD1d–glycolipid
complexes. All ligand contacts are represented schematically.
The polar core of the ligands is highlighted as a light red box.
Broken lines represent hydrogen bonds, gray circles show vdW
contacts, dashed circles indicate residues whose side chains
adopt two alternate conformations, and filled gray circles
highlight specific protein fluorine contacts. Ligand components
are color coded according to Fig. 1. Apolar interactions with
the F′-pocket are common to all ligands.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2009,
394,
71-82)
copyright 2009.
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