2M2D

Human programmed cell death 1 receptor

2M2D の概要

• エントリーDOI: 10.2210/pdb2m2d/pdb
• NMR情報: BMRB: 18908
• 分子名称: Programmed cell death protein 1 (1 entity in total)
• 機能のキーワード: pd-1, apoptosis
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: Q15116
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13245.81

構造登録者

Veverka, V.,Cheng, X.,Waters, L.C.,Muskett, F.W.,Morgan, S.,Lesley, A.,Griffiths, M.,Stubberfield, C.,Griffin, R.,Henry, A.J.,Robinson, M.K.,Jansson, A.,Ladbury, J.E.,Ikemizu, S.,Davis, S.J.,Carr, M.D. (登録日: 2012-12-18, 公開日: 2013-02-27, 最終更新日: 2024-10-30)

主引用文献

Cheng, X.,Veverka, V.,Radhakrishnan, A.,Waters, L.C.,Muskett, F.W.,Morgan, S.H.,Huo, J.,Yu, C.,Evans, E.J.,Leslie, A.J.,Griffiths, M.,Stubberfield, C.,Griffin, R.,Henry, A.J.,Jansson, A.,Ladbury, J.E.,Ikemizu, S.,Carr, M.D.,Davis, S.J.
Structure and interactions of the human programmed cell death 1 receptor.
J.Biol.Chem., 288:11771-11785, 2013

PubMed 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.

PubMed: 23417675
DOI: 10.1074/jbc.M112.448126

実験手法

SOLUTION NMR