Structure and interactions of the human programmed cell death 1 receptor.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Sprog: | English |
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2013
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| _version_ | 1826265811203915776 |
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| author | Cheng, X Veverka, V Radhakrishnan, A Waters, L Muskett, F Morgan, S Huo, J Yu, C Evans, E Leslie, A Griffiths, M Stubberfield, C Griffin, R Henry, A Jansson, A Ladbury, J Ikemizu, S Carr, MD Davis, S |
| author_facet | Cheng, X Veverka, V Radhakrishnan, A Waters, L Muskett, F Morgan, S Huo, J Yu, C Evans, E Leslie, A Griffiths, M Stubberfield, C Griffin, R Henry, A Jansson, A Ladbury, J Ikemizu, S Carr, MD Davis, S |
| author_sort | Cheng, X |
| collection | OXFORD |
| 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 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. |
| first_indexed | 2024-03-06T20:29:28Z |
| format | Journal article |
| id | oxford-uuid:30916cec-bf47-48df-847a-227a2afc144f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:29:28Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:30916cec-bf47-48df-847a-227a2afc144f2022-03-26T13:02:14ZStructure and interactions of the human programmed cell death 1 receptor.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:30916cec-bf47-48df-847a-227a2afc144fEnglishSymplectic Elements at Oxford2013Cheng, XVeverka, VRadhakrishnan, AWaters, LMuskett, FMorgan, SHuo, JYu, CEvans, ELeslie, AGriffiths, MStubberfield, CGriffin, RHenry, AJansson, ALadbury, JIkemizu, SCarr, MDDavis, SPD-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. |
| spellingShingle | Cheng, X Veverka, V Radhakrishnan, A Waters, L Muskett, F Morgan, S Huo, J Yu, C Evans, E Leslie, A Griffiths, M Stubberfield, C Griffin, R Henry, A Jansson, A Ladbury, J Ikemizu, S Carr, MD Davis, S Structure and interactions of the human programmed cell death 1 receptor. |
| title | Structure and interactions of the human programmed cell death 1 receptor. |
| title_full | Structure and interactions of the human programmed cell death 1 receptor. |
| title_fullStr | Structure and interactions of the human programmed cell death 1 receptor. |
| title_full_unstemmed | Structure and interactions of the human programmed cell death 1 receptor. |
| title_short | Structure and interactions of the human programmed cell death 1 receptor. |
| title_sort | structure and interactions of the human programmed cell death 1 receptor |
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