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Structure and Inter...
Structure and Interactions of the Human Programmed Cell Death 1 Receptor
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- 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
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- 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
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- 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
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- Muskett, Frederick W. (författare)
- Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom
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- 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
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- 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
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- 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
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- 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
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- Leslie, Alasdair J. (författare)
- Radcliffe Department of Medicine [Oxford]
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- Griffiths, Meryn (författare)
- UCB Pharma, Slough SL1 4EN, United Kingdom
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- Stubberfield, Colin (författare)
- UCB Pharma, Slough SL1 4EN, United Kingdom
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- Griffin, Robert (författare)
- UCB Pharma, Slough SL1 4EN, United Kingdom
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- Henry, Alistair J. (författare)
- UCB Pharma, Slough SL1 4EN, United Kingdom
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- Jansson, Andreas (författare)
- Högskolan i Skövde,Institutionen för vård och natur,Forskningscentrum för Systembiologi
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- Ladbury, John E. (författare)
- Högskolan i Skövde,Institutionen för vård och natur,Forskningscentrum för Systembiologi
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- Ikemizu, Shinji (författare)
- Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862 0973, Japan
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- Carr, Mark D. (författare)
- Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom
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- 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.
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 288:17, s. 11771-11785
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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)
Nyckelord
- Natural sciences
- Naturvetenskap
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Cheng, Xiaoxiao
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Veverka, Vaclav
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Radhakrishnan, A ...
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Waters, Lorna C.
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Muskett, Frederi ...
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Morgan, Sara H.
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visa fler...
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Huo, Jiandong
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Yu, Chao
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Evans, Edward J.
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Leslie, Alasdair ...
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Griffiths, Meryn
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Stubberfield, Co ...
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Griffin, Robert
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Henry, Alistair ...
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Jansson, Andreas
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Ladbury, John E.
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Ikemizu, Shinji
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Carr, Mark D.
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Davis, Simon J.
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