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PDBsum entry 2m2d
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References listed in PDB file
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Key reference
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Title
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Structure and interactions of the human programmed cell death 1 receptor.
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Authors
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X.Cheng,
V.Veverka,
A.Radhakrishnan,
L.C.Waters,
F.W.Muskett,
S.H.Morgan,
J.Huo,
C.Yu,
E.J.Evans,
A.J.Leslie,
M.Griffiths,
C.Stubberfield,
R.Griffin,
A.J.Henry,
A.Jansson,
J.E.Ladbury,
S.Ikemizu,
M.D.Carr,
S.J.Davis.
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Ref.
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J Biol Chem, 2013,
288,
11771-11785.
[DOI no: ]
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PubMed id
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Abstract
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PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent
regulator of immune responses and a promising therapeutic target. The structure
and interactions of human PD-1 are, however, incompletely characterized. We
present the solution nuclear magnetic resonance (NMR)-based structure of the
human PD-1 extracellular region and detailed analyses of its interactions with
its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily
topology but differs at the edge of the GFCC' sheet, which is flexible and
completely lacks a C″ strand. Changes in PD-1 backbone NMR signals induced by
ligand binding suggest that, whereas binding is centered on the GFCC' sheet,
PD-1 is engaged by its two ligands differently and in ways incompletely
explained by crystal structures of mouse PD-1·ligand complexes. The affinities
of these interactions and that of PD-L1 with the costimulatory protein B7-1,
measured using surface plasmon resonance, are significantly weaker than
expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is
principally due to the 3-fold smaller dissociation rate for PD-L2 binding.
Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is
entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component.
Mathematical simulations based on the biophysical data and quantitative
expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1
ligation during interactions of activated T cells with antigen-presenting cells.
These findings provide a rigorous structural and biophysical framework for
interpreting the important functions of PD-1 and reveal that potent inhibitory
signaling can be initiated by weakly interacting receptors.
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