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Structure and Interactions of the Human Programmed Cell Death 1 Receptor
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom, the Institute of Organic Chemistry and Biochemistry, Flemingovo Namesti 2, 166 10 Prague 6, Czech Republic.
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 17, p. 11771-11785Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2013. Vol. 288, no 17, p. 11771-11785
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Biochemistry and Molecular Biology Cancer and Oncology
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Natural sciences
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URN: urn:nbn:se:his:diva-8400DOI: 10.1074/jbc.M112.448126ISI: 000318157600014PubMedID: 23417675Scopus ID: 2-s2.0-84876924130OAI: oai:DiVA.org:his-8400DiVA, id: diva2:640435
Available from: 2013-08-13 Created: 2013-08-13 Last updated: 2021-08-31Bibliographically approved

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Jansson, Andreas

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