PDBsum entry 2m2d

Apoptosis

PDB id: 2m2d

Contents

Protein chain

118 a.a.

PDB id:

2m2d

Name:

Apoptosis

Title:

Human programmed cell death 1 receptor

Structure:

Programmed cell death protein 1. Chain: a. Synonym: protein pd-1, hpd-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pdcd1, pd1. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

35 models

Authors:

V.Veverka,X.Cheng,L.C.Waters,F.W.Muskett,S.Morgan,A.Lesley, M.Griffiths,C.Stubberfield,R.Griffin,A.J.Henry,M.K.Robinson, A.Jansson,J.E.Ladbury,S.Ikemizu,S.J.Davis,M.D.Carr

Key ref:

X.Cheng et al. (2013). Structure and interactions of the human programmed cell death 1 receptor. J Biol Chem, 288, 11771-11785. PubMed id: 23417675 DOI: 10.1074/jbc.M112.448126

Date:

18-Dec-12 Release date: 27-Feb-13

Protein chain

Q15116  (PDCD1_HUMAN) -  Programmed cell death protein 1 from Homo sapiens

Seq: 288 a.a.

Struc: 118 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1074/jbc.M112.448126

J Biol Chem 288:11771-11785 (2013)

PubMed id: 23417675

Structure and interactions of the human programmed cell death 1 receptor.

X.Cheng, V.Veverka, A.Radhakrishnan, L.C.Waters, F.W.Muskett, S.H.Morgan, J.Huo, C.Yu, E.J.Evans, A.J.Leslie, M.Griffiths, C.Stubberfield, R.Griffin, A.J.Henry, A.Jansson, J.E.Ladbury, S.Ikemizu, M.D.Carr, S.J.Davis.

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.