Structure and interactions of the human programmed cell death 1 receptor

Xiaoxiao Cheng, Vaclav Veverka, Anand Radhakrishnan, Lorna C. Waters, Frederick W. Muskett, Sara H. Morgan, Jiandong Huo, Chao Yu, Edward J. Evans, Alasdair J. Leslie, Meryn Griffiths, Colin Stubberfield, Robert Griffin, Alistair J. Henry, Andreas Jansson, John E. Ladbury, Shinji Ikemizu, Mark D. Carr, Simon J. Davis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

150 Scopus citations

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 GFCCα 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 GFCCα 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.

Original languageEnglish (US)
Pages (from-to)11771-11785
Number of pages15
JournalJournal of Biological Chemistry
Volume288
Issue number17
DOIs
StatePublished - Apr 26 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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