title: Structure and interactions of the human programmed cell death 1 receptor.
abstract: 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.
authors: Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
authors: Xiaoxiao
authors: X
authors: Cheng
authors: Vaclav
authors: V
authors: Veverka
authors: Anand
authors: A
authors: Radhakrishnan
authors: Lorna C
authors: LC
authors: Waters
authors: Frederick W
authors: FW
authors: Muskett
authors: Sara H
authors: SH
authors: Morgan
authors: Jiandong
authors: J
authors: Huo
authors: Chao
authors: C
authors: Yu
authors: Edward J
authors: EJ
authors: Evans
authors: Alasdair J
authors: AJ
authors: Leslie
authors: Meryn
authors: M
authors: Griffiths
authors: Colin
authors: C
authors: Stubberfield
authors: Robert
authors: R
authors: Griffin
authors: Alistair J
authors: AJ
authors: Henry
authors: Andreas
authors: A
authors: Jansson
authors: John E
authors: JE
authors: Ladbury
authors: Shinji
authors: S
authors: Ikemizu
authors: Mark D
authors: MD
authors: Carr
authors: Simon J
authors: SJ
authors: Davis
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D006801:Humans; D051379:Mice; D018448:Models, Immunological; D019906:Nuclear Magnetic Resonance, Biomolecular; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor