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Publication Abstract from PubMed

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-A 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 the molecule. 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.

Structural insight into T cell coinhibition by PD-1H (VISTA).,Slater BT, Han X, Chen L, Xiong Y Proc Natl Acad Sci U S A. 2020 Jan 9. pii: 1908711117. doi:, 10.1073/pnas.1908711117. PMID:31919279^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.