期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 30, 页码 10483-10488出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0804453105
关键词
costimulation; coinhibition; inhibitory receptor; T cell activation
资金
- NCI NIH HHS [P30 CA013330, P30CA013330] Funding Source: Medline
- NIAID NIH HHS [R01 AI007289, R56 AI007289, AI07289] Funding Source: Medline
- NIBIB NIH HHS [P30 EB009998] Funding Source: Medline
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.
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