2m2d
Human programmed cell death 1 receptor
Structural highlights
DiseasePDCD1_HUMAN Systemic lupus erythematosus;Multiple sclerosis. Systemic lupus erythematosus 2 (SLEB2) [MIM:605218: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[1] FunctionPDCD1_HUMAN Inhibitory cell surface receptor involved in the regulation of T-cell function during immunity and tolerance. Upon ligand binding, inhibits T-cell effector functions in an antigen-specific manner. Possible cell death inducer, in association with other factors.[2] Publication Abstract from PubMedPD-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, whilst binding is centred 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 three- to four-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the three-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 signalling can be initiated by weakly interacting receptors. Structure and interactions of the human programmed cell death 1 receptor.,Cheng X, Veverka V, Radhakrishnan A, Waters LC, Muskett FW, Morgan S, Huo J, Yu C, Evans EJ, Leslie AJ, Griffiths M, Stubberfield C, Griffin R, Henry AJ, Jansson A, Ladbury JE, Ikemizu S, Carr MD, Davis SJ J Biol Chem. 2013 Feb 15. PMID:23417675[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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