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Structure and Interactions of the Human Programmed Cell Death 1 Receptor

Cheng, Xiaoxiao (författare)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Veverka, Vaclav (författare)
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
Radhakrishnan, Anand (författare)
Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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Waters, Lorna C. (författare)
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom
Muskett, Frederick W. (författare)
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom
Morgan, Sara H. (författare)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Huo, Jiandong (författare)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Yu, Chao (författare)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Evans, Edward J. (författare)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
Leslie, Alasdair J. (författare)
Radcliffe Department of Medicine [Oxford]
Griffiths, Meryn (författare)
UCB Pharma, Slough SL1 4EN, United Kingdom
Stubberfield, Colin (författare)
UCB Pharma, Slough SL1 4EN, United Kingdom
Griffin, Robert (författare)
UCB Pharma, Slough SL1 4EN, United Kingdom
Henry, Alistair J. (författare)
UCB Pharma, Slough SL1 4EN, United Kingdom
Jansson, Andreas (författare)
Högskolan i Skövde,Institutionen för vård och natur,Forskningscentrum för Systembiologi
Ladbury, John E. (författare)
Högskolan i Skövde,Institutionen för vård och natur,Forskningscentrum för Systembiologi
Ikemizu, Shinji (författare)
Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862 0973, Japan
Carr, Mark D. (författare)
Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom
Davis, Simon J. (författare)
Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom
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 (creator_code:org_t)
American Society for Biochemistry and Molecular Biology, 2013
2013
Engelska.
Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 288:17, s. 11771-11785
Relaterad länk:
https://doi.org/10.1...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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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.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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Natural sciences
Naturvetenskap

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