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Title: Structural insight into T cell coinhibition by PD-1H (VISTA)

Abstract

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-Å 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” β-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.

Authors:
ORCiD logo; ORCiD logo; ORCiD logo; ORCiD logo
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1582072
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 117 Journal Issue: 3; Journal ID: ISSN 0027-8424
Publisher:
Proceedings of the National Academy of Sciences
Country of Publication:
United States
Language:
English

Citation Formats

Slater, Benjamin T., Han, Xue, Chen, Lieping, and Xiong, Yong. Structural insight into T cell coinhibition by PD-1H (VISTA). United States: N. p., 2020. Web. doi:10.1073/pnas.1908711117.
Slater, Benjamin T., Han, Xue, Chen, Lieping, & Xiong, Yong. Structural insight into T cell coinhibition by PD-1H (VISTA). United States. doi:10.1073/pnas.1908711117.
Slater, Benjamin T., Han, Xue, Chen, Lieping, and Xiong, Yong. Thu . "Structural insight into T cell coinhibition by PD-1H (VISTA)". United States. doi:10.1073/pnas.1908711117.
@article{osti_1582072,
title = {Structural insight into T cell coinhibition by PD-1H (VISTA)},
author = {Slater, Benjamin T. and Han, Xue and Chen, Lieping and Xiong, Yong},
abstractNote = {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-Å 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” β-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.},
doi = {10.1073/pnas.1908711117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 3,
volume = 117,
place = {United States},
year = {2020},
month = {1}
}

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