Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2

Abstract

Programmed death-1 (PD-1) is a member of the CD28/B7 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. The high-resolution crystal structure of the complex formed by the complete ectodomains of murine PD-1 and PD-L2 revealed a 1:1 receptor:ligand stoichiometry and displayed a binding interface and overall molecular organization distinct from that observed in the CTLA-4/B7 inhibitory complexes. Furthermore, our structure also provides insights into the association between PD-1 and PD-L1 and highlights differences in the interfaces formed by the two PD-1 ligands (PD-Ls) Mutagenesis studies confirmed the details of the proposed PD-1/PD-L binding interfaces and allowed for the design of a mutant PD-1 receptor with enhanced affinity. These studies define spatial and organizational constraints that control the localization and signaling of PD-1/PD-L complexes within the immunological synapse and provide a basis for manipulating the PD-1 pathways for immunotherapy.costimulation ͉ coinhibition ͉ inhibitory receptor ͉ T cell activation

Programmed death ligand -1: a review

“…The molecule is well defined by electron density, safe for a region between C′D strands. However, previous reports done by Lázár [4,5,6] .…”

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

“…S2A). Previous studies identified several human PD-1 residues as critical for PD-L1 and PD-L2 binding (31)(32)(33)(34), and these residues are contained within the two sequences (Supplementary Fig. S2B).…”

Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek

“…Eight of 14 aa involved in binding to PD-1 are identical or highly conserved between PD-L1 and PD-L2. Trp-110 in the middle of the G strand of PD-L2 is an Ala in PD-L1, and mutational analysis suggests that this accounts for much of the 3-fold-higher affinity of PD-L2 for PD-1 (6,14). Binding face to face establishes an acute angle between PD-1 and PD-L1 or PD-L2, as opposed to the right angle between CTLA4 and B7-1.…”

“…The role of the PD-1 pathway in peripheral T cell tolerance and its role in immune evasion by tumors and chronic infections make the PD-1 pathway a promising therapeutic target. Two recent papers have determined the structures of the PD-1/PD-L1 (5) and PD-1/PD-L2 complexes [see Lazar-Molnar et al (6) in this issue of PNAS].…”