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* Residue conservation analysis
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PDB id:
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Immune system
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Title:
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Crystal structure of the pd-1/pd-l1 complex
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Structure:
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Programmed cell death 1 ligand 1. Chain: a. Fragment: extracellular region. Synonym: programmed death ligand 1, pd-l1, pdcd1 ligand 1, b7 homolog 1, b7-h1, cd274 antigen. Engineered: yes. Programmed cell death protein 1. Chain: b, c. Fragment: extracellular domain.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: cd274, b7h1, pdcd1l1, pdcd1lg1, pdl1. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. House mouse. Organism_taxid: 10090.
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Resolution:
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2.65Å
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R-factor:
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0.214
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R-free:
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0.268
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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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Key ref:
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D.Y.Lin
et al.
(2008).
The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors.
Proc Natl Acad Sci U S A,
105,
3011-3016.
PubMed id:
DOI:
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Date:
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30-Nov-07
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Release date:
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26-Feb-08
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PROCHECK
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Headers
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References
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DOI no:
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Proc Natl Acad Sci U S A
105:3011-3016
(2008)
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PubMed id:
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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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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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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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Selected figure(s)
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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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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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C.Yu,
A.F.Sonnen,
R.George,
B.H.Dessailly,
L.J.Stagg,
E.J.Evans,
C.A.Orengo,
D.I.Stuart,
J.E.Ladbury,
S.Ikemizu,
R.J.Gilbert,
and
S.J.Davis
(2011).
Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.
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J Biol Chem,
286,
6685-6696.
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L.Wang,
R.Rubinstein,
J.L.Lines,
A.Wasiuk,
C.Ahonen,
Y.Guo,
L.F.Lu,
D.Gondek,
Y.Wang,
R.A.Fava,
A.Fiser,
S.Almo,
and
R.J.Noelle
(2011).
VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses.
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J Exp Med,
208,
577-592.
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M.G.Joyce,
P.Tran,
M.A.Zhuravleva,
J.Jaw,
M.Colonna,
and
P.D.Sun
(2011).
Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site.
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Proc Natl Acad Sci U S A,
108,
6223-6228.
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M.Iwasaki,
Y.Tanaka,
H.Kobayashi,
K.Murata-Hirai,
H.Miyabe,
T.Sugie,
M.Toi,
and
N.Minato
(2011).
Expression and function of PD-1 in human γδ T cells that recognize phosphoantigens.
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Eur J Immunol,
41,
345-355.
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Y.Li,
Q.Wang,
and
R.A.Mariuzza
(2011).
Structure of the human activating natural cytotoxicity receptor NKp30 bound to its tumor cell ligand B7-H6.
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J Exp Med,
208,
703-714.
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E.A.Said,
F.P.Dupuy,
L.Trautmann,
Y.Zhang,
Y.Shi,
M.El-Far,
B.J.Hill,
A.Noto,
P.Ancuta,
Y.Peretz,
S.G.Fonseca,
J.Van Grevenynghe,
M.R.Boulassel,
J.Bruneau,
N.H.Shoukry,
J.P.Routy,
D.C.Douek,
E.K.Haddad,
and
R.P.Sekaly
(2010).
Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection.
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Nat Med,
16,
452-459.
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M.Ghiotto,
L.Gauthier,
N.Serriari,
S.Pastor,
A.Truneh,
J.A.Nunès,
and
D.Olive
(2010).
PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1.
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Int Immunol,
22,
651-660.
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R.L.Rich,
and
D.G.Myszka
(2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
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J Mol Recognit,
23,
1.
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K.Chattopadhyay,
E.Lazar-Molnar,
Q.Yan,
R.Rubinstein,
C.Zhan,
V.Vigdorovich,
U.A.Ramagopal,
J.Bonanno,
S.G.Nathenson,
and
S.C.Almo
(2009).
Sequence, structure, function, immunity: structural genomics of costimulation.
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Immunol Rev,
229,
356-386.
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T.Pentcheva-Hoang,
E.Corse,
and
J.P.Allison
(2009).
Negative regulators of T-cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections.
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Immunol Rev,
229,
67-87.
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Y.Chen,
Y.Shi,
H.Cheng,
Y.Q.An,
and
G.F.Gao
(2009).
Structural immunology and crystallography help immunologists see the immune system in action: how T and NK cells touch their ligands.
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IUBMB Life,
61,
579-590.
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E.Lázár-Molnár,
Q.Yan,
E.Cao,
U.Ramagopal,
S.G.Nathenson,
and
S.C.Almo
(2008).
Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2.
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Proc Natl Acad Sci U S A,
105,
10483-10488.
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PDB codes:
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G.J.Freeman
(2008).
Structures of PD-1 with its ligands: sideways and dancing cheek to cheek.
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Proc Natl Acad Sci U S A,
105,
10275-10276.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
