PDBsum entry 3gmm

Immune system

PDB id: 3gmm

Contents

Protein chains

268 a.a. *

99 a.a. *

Ligands

NAG-NAG-BMA-MAN-MAN

NAG-NAG-BMA-MAN-MAN-FUC

NAG

C8P

PLM

EDO ×4

Waters ×320

* Residue conservation analysis

PDB id:

3gmm

Name:

Immune system

Title:

Structure of mouse cd1d in complex with c8ph

Structure:

T-cell surface glycoprotein cd1d1. Chain: a. Fragment: unp residues 19-297. Engineered: yes. Beta-2 microglobulin. Chain: b. Fragment: unp residues 21-119. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: cd1d1, cd1.1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: b2m.

Resolution:

1.80Å R-factor: 0.177 R-free: 0.219

Authors:

A.Schiefner,I.A.Wilson

Key ref:

A.Schiefner et al. (2009). Structural evaluation of potent NKT cell agonists: implications for design of novel stimulatory ligands. J Mol Biol, 394, 71-82. PubMed id: 19732779 DOI: 10.1016/j.jmb.2009.08.061

Date:

14-Mar-09 Release date: 10-Nov-09

Protein chain

P11609  (CD1D1_MOUSE) -  Antigen-presenting glycoprotein CD1d1 from Mus musculus

Seq: 336 a.a.

Struc: 268 a.a.*

Protein chain

P01887  (B2MG_MOUSE) -  Beta-2-microglobulin from Mus musculus

Seq: 119 a.a.

Struc: 99 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1016/j.jmb.2009.08.061

J Mol Biol 394:71-82 (2009)

PubMed id: 19732779

Structural evaluation of potent NKT cell agonists: implications for design of novel stimulatory ligands.

A.Schiefner, M.Fujio, D.Wu, C.H.Wong, I.A.Wilson.

ABSTRACT

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 394, 71-82) copyright 2009.

Figures were selected by an automated process.