Cargando…
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...
Autores principales: | , |
---|---|
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 |
_version_ | 1783477369030311936 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6900541 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT tangshaogeng ahighaffinityhumanpd1pdl2complexinformsavenuesforsmallmoleculeimmunecheckpointdrugdiscovery AT kimpeters ahighaffinityhumanpd1pdl2complexinformsavenuesforsmallmoleculeimmunecheckpointdrugdiscovery AT tangshaogeng highaffinityhumanpd1pdl2complexinformsavenuesforsmallmoleculeimmunecheckpointdrugdiscovery AT kimpeters highaffinityhumanpd1pdl2complexinformsavenuesforsmallmoleculeimmunecheckpointdrugdiscovery |