PDBsum entry 1fv1

Immune system

PDB id: 1fv1

Contents

Protein chains

179 a.a. *

190 a.a. *

20 a.a. *

18 a.a. *

Ligands

SO4 ×3

GOL ×2

Waters ×494

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structural basis for the binding of an immunodominant peptide from myelin basic protein in different registers by two hla-Dr2 proteins.

Authors

Y.Li, H.Li, R.Martin, R.A.Mariuzza.

Ref.

J Mol Biol, 2000, 304, 177-188. [DOI no: 10.1006/jmbi.2000.4198]

PubMed id

11080454

Abstract

Susceptibility to multiple sclerosis (MS) is associated with certain MHC class II haplotypes, in particular HLA-DR2. Two DR beta chains, DRB1*1501 and DRB5*0101, are co-expressed in the HLA-DR2 haplotype, resulting in the formation of two functional cell surface heterodimers, HLA-DR2a (DRA*0101, DRB5*0101) and HLA-DR2b (DRA*0101, DRB1*1501). Both isotypes can present an immunodominant peptide of myelin basic protein (MBP 84-102) to MBP-specific T cells from MS patients. We have determined the crystal structure of HLA-DR2a complexed with MBP 86-105 to 1.9 A resolution. A comparison of this structure with that of HLA-DR2b complexed with MBP 85-99, reported previously, reveals that the peptide register is shifted by three residues, such that the MBP peptide is bound in strikingly different conformations by the two MHC molecules. This shift in binding register is attributable to a large P1 pocket in DR2a, which accommodates Phe92, in conjunction with a relatively shallow P4 pocket, which is occupied by Ile95. In DR2b, by contrast, the small P1 pocket accommodates Val89, while the deep P4 pocket is filled by Phe92. In both complexes, however, the C-terminal half of the peptide is positioned higher in the binding groove than in other MHC class II/peptide structures. As a result of the register shift, different side-chains of the MBP peptide are displayed for interaction with T cell receptors in the DR2a and DR2b complexes. These results demonstrate that MHC molecules can impose different alignments and conformations on the same bound peptide as a consequence of topological differences in their peptide-binding sites, thereby creating distinct T cell epitopes.

Figure 1.
Figure 1. (a) Electron density for the bound peptide in the HLA-DR2a/MBP 86-105 complex. The Fo - Fc omit map at 1.9 Å resolution is contoured at 2s. (b) Superposition of the MBP 86-105 peptide (red) bound by HLA-DR2a onto the MBP 85-99 peptide (green) bound by HLA-DR2b (Smith et al., 1998). (c) Alignment of MBP 86-105 and MBP 85- 99 according to their registers in the peptide-binding grooves of HLA-DR2a and HLA-DR2b, respectively.

Figure 3.
Figure 3. (a) Superposition of peptides bound to human MHC class II molecules. The MBP 86-105 pep- tide bound to HLA-DR2a is red and the MBP 85-99 pep- tide bound to HLA-DR2b (Smith et al., 1998) is green. In yellow are peptides bound to other HLA-DR molecules: DR1 (Stern et al., 1994), DR3 (Ghosh et al., 1995) and DR4 (Dessen et al., 1997). HLA-DR2a is shown in gray. The peptide backbones superpose well from P-2 to P4, but display considerable divergence beginning at P6. In particular, the C-terminal portions of the MBP peptides presented by DR2a and DR2b are positioned higher in the binding groove than the C-terminal portions of pep- tides presented by DR1, DR3, or DR4. (b) Confor- mations of Trp61b in HLA-DR2a and HLA-DR3. In red are the MBP peptide bound to HLA-DR2a and the side- chains of residues Trp61b and Leu38b of this DR. In yel- low are CLIP peptide bound to HLA-DR3 (Ghosh et al., 1995) and the side-chains of Trp61b and Val38b. HLA- DR2a and HLA-DR3 are gray and blue, respectively. Superpositions were done using the a1 and b1 domains of the DR molecules.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 304, 177-188) copyright 2000.