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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Structure and interactions of the human programmed cell death 1 receptor
Journal of Biological Chemistry, Volume 288, No. 17, Year 2013
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Description
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 GFCCα 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 GFCCα 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.
Authors & Co-Authors
Veverka, V.
United Kingdom, Leicester
University of Leicester
Czech Republic, Prague
Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic
Radhakrishnan, Anand K.
United States, Houston
The University of Texas Md Anderson Cancer Center
Muskett, Frederick W.
United Kingdom, Leicester
University of Leicester
Huo, Jiangdong
United Kingdom, Oxford
John Radcliffe Hospital
United Kingdom, London
Medical Research Council
Leslie, Alasdair J.
United Kingdom, Oxford
John Radcliffe Hospital
Davis, Simon J.
United Kingdom, Oxford
John Radcliffe Hospital
United Kingdom, London
Medical Research Council
Statistics
Citations: 227
Authors: 6
Affiliations: 8
Identifiers
Doi:
10.1074/jbc.M112.448126
ISSN:
1083351X
Research Areas
Cancer
Study Approach
Quantitative