Structure of HLA-A*1101 in complex with a hepatitis B peptide homologue

Abstract

A high-resolution structure of the human MHC-I molecule HLA-A*1101 is presented in which it forms a complex with a sequence homologue of a peptide that occurs naturally in hepatitis B virus DNA polymerase. The sequence of the bound peptide is AIMPARFYPK, while that of the corresponding natural peptide is LIMPARFYPK. The peptide does not make efficient use of the middle E pocket for binding, which leads to a rather superficial and exposed binding mode for the central peptide residues. Despite this, the peptide binds with high affinity (IC50 of 31 nM).

Figure 1

Electron density of the AIMPARFYPK peptide. The electron density is contoured at 1σ and clearly shows density for all of the peptide including the additional N-terminal alanine (left). The peptide is coloured according to B values from blue to red (13–48 Ų). (a) Side view, (b) top view. All figures were prepared with PyMOL (DeLano, 2002 ▶).

Figure 2

Schematic overview of the structure of HLA-A*1101 in complex with the AIMPARFYPK peptide. The AIMPARFYPK peptide (red; labelled ‘p’) is viewed from the N-terminal end. The α-chain is shown in grey with individual subdomains indicated; β₂-microglobulin is in blue. Notice the relatively exposed position of the peptide in the binding groove.

Figure 3

A T-cell view of the bound AIMPARFYPK peptide of the HLA-A*1101 complex. Binding pockets are indicated with colours: A, green; B, cyan; C, red; D, yellow; E, orange; F, blue. The peptide and selected water molecules suggested to be important for peptide binding are shown in white (see also Table 4 ▶). Notice the large number of water molecules beneath the peptide and that Pro4p covers Met3p.

Figure 4

The peptide positions in the binding groove after superimposition of MHC complex structures. The C^α atoms of the peptides have been connected and α-chain residues have been removed for clarity. (a) The AIMPARFYPK peptide (red, numbered) follows a relatively superficial path, whereas other decamer peptides bound by A3 supertype molecules [green, HLA-A*6801 complex (PDB code 1tmc; Collins et al., 1995 ▶); cyan, HLA-A*1101 complex (PDB code 1qvo; Li & Bouvier, 2004 ▶)] achieve a deeper position by placing residue 6 in the E pocket (indicated with an E). Complexes with nonamer peptides [yellow, HLA-A*1101 complex (PDB code 1q94; Li & Bouvier, 2004 ▶); green, HLA-A*1101 complex (PDB code 1x7q; Blicher et al., 2005 ▶)] utilize residue 5 for binding in the E pocket in a similar fashion. (b) Comparison of the AIMPARFYPK peptide (red) with two decamer peptides [purple, HLA-A*0201 complex (PDB code 1i4f; Hillig et al., 2001 ▶); orange, HLA-B*2705 (PDB code 2bss; Stewart-Jones, Di Gleria et al., 2005 ▶)] and two 11-residue peptides [blue, HLA-B*5703 (PDB code 2bvo; Stewart-Jones, Gillespie et al., 2005 ▶); green, HLA-B*3501 (PDB code 1zsd; Miles et al., 2005 ▶)] bound by other HLA alleles. Although the AIMPARFYPK peptide bulges out of the groove, it is not unusual for a decamer peptide. The orientation is the same as in (a).