The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors - PubMed (original) (raw)

The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

David Yin-Wei Lin et al. Proc Natl Acad Sci U S A. 2008.

Abstract

Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives "exhausted" virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Two views of the PD-1/PD-L1 complex. The two single-domain PD-1 molecules in the asymmetric unit of the crystal are shown in red (PD-1) and violet (second PD-1). The two-domain PD-L1 molecule is shown in blue. The strands of the two β-sheets of PD-1 are labeled ABED and A′GFCC′C″. The strands of the two β-sheets of the PD-L1 V domain are labeled AGFCC′C″ and BED. Note the tenuous contacts that the second PD-1 makes to PD-1 and PD-L1, seen best on the right side of the figure. N-linked glycosylation sites (gold) are at PD-1 residues 49, 58, 74, and 116 and at PD-L1 residue 35. Carbohydrate at any of the five potential sites is predicted not to interfere with the formation of the complex. The view at right is after a rotation of 45° around the vertical axis. The N and C termini are identified.

Fig. 2.

Fig. 2.

The PD-1/PD-L1 interface. Shown is a stereoview of the PD-1/PD-L1 interface showing side chains of residues on β-strands (CC′FG) of PD-1 (red) and on β-strands (GFCC′, left to right) of PD-L1 (blue) that make contacts. Interacting PD-1 side chains (pink) and PD-L1 (light blue) are shown; for clarity a few side chains are not shown. Dotted lines (yellow) indicate hydrogen bonds formed in the interface and with a water molecule.

Fig. 3.

Fig. 3.

The IgV domains of PD1/PD-L1 are similar to antigen receptors. (A) The loops at the ends of the PD-1 domain and the first domain of PD-L1 are located on the same side of the complex. (B) For comparison, the Fv or VHVL portion of a representative antibody [PDB ID code 1G7J (31)] found in the search of the database was superimposed on the Fv-like portion of the PD-1/PD-L1 complex to yield an rms difference of 2.6 Å over 180 pairs of α-carbon pairs. (C) The VαVβ portion of a representative TCR [PDB ID code 2BNU (32)] was superimposed on the Fv-like part of the PD-1/PD-L1 complex with an rms difference of 3.1 Å over 191 Cα pairs. In B and C, after superimposing on to PD-1/PD-L1, the models were translated apart for viewing. The loops that are antigen receptor CDRs are labeled (CDR1, CDR2, and CDR3). The search of the database was performed with the PD-1/PD-L1 Fv-like domain as query and all of the targets considered as two-domain rigid bodies.

Fig. 4.

Fig. 4.

A comparison of the PD-1/PD-L1 and CTLA-4/B7-1 variable-like (V) domain interactions. (Left) the two complexes were overlaid by superimposing PD-1 (red) on to CTLA-4 (green), then translated apart vertically for viewing. (Right) The two complexes were rotated by 180°. Note the marked difference in the location of the B7-1 V domain (yellow) in comparison to the V domain of PD-L1 (blue).

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