期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 3, 页码 1648-1657出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1908711117
关键词
PD-1H; VISTA; structure; T cell coinhibition; cancer immunotherapy
资金
- Boehringer Ingelheim
- NIH [P50 CA196530, P30 CA016359]
- United Technologies Corporation Endowed Chair
- National Institute of General Medical Sciences from the National Institutes of Health [P30 GM124165]
- NIH-Office of Research Infrastructure Programs High-End Instrumentation grant [S10OD021527]
- Department of Energy Office of Science [DE-AC02-06CH11357]
Programmed death-1 homolog (PD-1H), a CD28/B7 family molecule, coinhibits T cell activation and is an attractive immunotherapeutic target for cancer and inflammatory diseases. The molecular basis of its function, however, is unknown. Bioinformatic analyses indicated that PD-1H has a very long Ig variable region (IgV)-like domain and extraordinarily high histidine content, suggesting that unique structural features may contribute to coinhibitory mechanisms. Here we present the 1.9-angstrom crystal structure of the human PD-1H extracellular domain. It reveals an elongated CC' loop and a striking concentration of histidine residues, located in the complementarity-determining region-like proximal half of themolecule. We show that surface-exposed histidine clusters are essential for robust inhibition of T cell activation. PD-1H exhibits a noncanonical IgV-like topology including an extra H beta-strand and clamping disulfide, absent in known IgV-like structures, that likely restricts its orientation on the cell surface differently from other IgV-like domains. These results provide important insight into a molecular basis of T cell coinhibition by PD-1H.
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