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PDBsum entry 3bik
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Immune system
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PDB id
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3bik
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References listed in PDB file
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Key reference
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Title
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The pd-1/pd-L1 complex resembles the antigen-Binding fv domains of antibodies and t cell receptors.
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Authors
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D.Y.Lin,
Y.Tanaka,
M.Iwasaki,
A.G.Gittis,
H.P.Su,
B.Mikami,
T.Okazaki,
T.Honjo,
N.Minato,
D.N.Garboczi.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
3011-3016.
[DOI no: ]
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PubMed id
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Abstract
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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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Figure 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.
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Figure 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.
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