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

Eszter Lázár-Molnár, Qingrong Yan, Erhu Cao, Udupi Ramagopal, Stanley G Nathenson, Steven C Almo

Proceedings of the National Academy of Sciences of the United States of America 2008 Jul 29

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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.

Citation

Eszter Lázár-Molnár, Qingrong Yan, Erhu Cao, Udupi Ramagopal, Stanley G Nathenson, Steven C Almo. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proceedings of the National Academy of Sciences of the United States of America. 2008 Jul 29;105(30):10483-8