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A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery

Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-P...

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Autores principales: Tang, Shaogeng, Kim, Peter S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900541/
https://www.ncbi.nlm.nih.gov/pubmed/31727844
http://dx.doi.org/10.1073/pnas.1916916116
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author Tang, Shaogeng
Kim, Peter S.
author_facet Tang, Shaogeng
Kim, Peter S.
author_sort Tang, Shaogeng
collection PubMed
description Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC′ and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1’s affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC′ and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC′ loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.
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spelling pubmed-69005412019-12-12 A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery Tang, Shaogeng Kim, Peter S. Proc Natl Acad Sci U S A Biological Sciences Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC′ and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1’s affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC′ and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC′ loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors. National Academy of Sciences 2019-12-03 2019-11-14 /pmc/articles/PMC6900541/ /pubmed/31727844 http://dx.doi.org/10.1073/pnas.1916916116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Tang, Shaogeng
Kim, Peter S.
A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
title A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
title_full A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
title_fullStr A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
title_full_unstemmed A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
title_short A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
title_sort high-affinity human pd-1/pd-l2 complex informs avenues for small-molecule immune checkpoint drug discovery
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900541/
https://www.ncbi.nlm.nih.gov/pubmed/31727844
http://dx.doi.org/10.1073/pnas.1916916116
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