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Structure. 2017 Aug 1;25(8):1163-1174. doi: 10.1016/j.str.2017.06.011.

Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2.

Author information

1
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
2
Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
3
Department for Drug Design, University of Groningen, A. Deusinglaan 9, AV 9713 Groningen, the Netherlands.
4
Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland; Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland; Max Planck Institute for Biochemistry, Am Klopferspitz 18a, 82152 Martinsried, Germany. Electronic address: holak@chemia.uj.edu.pl.

Abstract

Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against cancer. In this review, we describe the latest work on structural characterization of the checkpoint proteins, their interactions with cognate ligands and with therapeutic antibodies. Structures of the extracellular portions of these proteins reveal that they all have a similar modular structure, composed of small domains similar in topology to the domains found in antibodies. Structural basis for blocking the PD-1/PD-L1 interaction by small molecules is illustrated with the compound BMS-202 that binds to and induces dimerization of PD-L1.

KEYWORDS:

PD-1; PD-L1; PD-L2; cancer; immune checkpoint; immunotherapy; nivolumab; pembrolizumab; small-molecule inhibitor; therapeutic antibody

PMID:
28768162
DOI:
10.1016/j.str.2017.06.011
[Indexed for MEDLINE]

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