Human and mouse PD-L1: similar molecular structure, but different druggability profiles
Summary: In the development of PD-L1-blocking therapeutics, it is essential to transfer initial in vitro findings into proper in vivo animal models. Classical immunocompetent mice are attractive due to high accessibility and low experimental costs. However, it is unknown whether inter-species differ...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220311573 |
| _version_ | 1818600538696056832 |
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| author | Katarzyna Magiera-Mularz Justyna Kocik Bogdan Musielak Jacek Plewka Dominik Sala Monika Machula Przemyslaw Grudnik Malgorzata Hajduk Marcin Czepiel Maciej Siedlar Tad A. Holak Lukasz Skalniak |
| author_facet | Katarzyna Magiera-Mularz Justyna Kocik Bogdan Musielak Jacek Plewka Dominik Sala Monika Machula Przemyslaw Grudnik Malgorzata Hajduk Marcin Czepiel Maciej Siedlar Tad A. Holak Lukasz Skalniak |
| author_sort | Katarzyna Magiera-Mularz |
| collection | DOAJ |
| description | Summary: In the development of PD-L1-blocking therapeutics, it is essential to transfer initial in vitro findings into proper in vivo animal models. Classical immunocompetent mice are attractive due to high accessibility and low experimental costs. However, it is unknown whether inter-species differences in PD-L1 sequence and structure would allow for human-mouse cross applications. Here, we disclose the first structure of the mouse (m) PD-L1 and analyze its similarity to the human (h) PD-L1. We show that mPD-L1 interacts with hPD-1 and provides a negative signal toward activated Jurkat T cells. We also show major differences in druggability between the hPD-L1 and mPD-L1 using therapeutic antibodies, a macrocyclic peptide, and small molecules. Our study indicates that while the amino acid sequence is well conserved between the hPD-L1 and mPD-L1 and overall structures are almost identical, crucial differences determine the interaction with anti-PD-L1 agents, that cannot be easily predicted in silico. |
| first_indexed | 2024-12-16T12:37:05Z |
| format | Article |
| id | doaj.art-60bd188bec4540759a79eec5931735b6 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-16T12:37:05Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-60bd188bec4540759a79eec5931735b62022-12-21T22:31:32ZengElsevieriScience2589-00422021-01-01241101960Human and mouse PD-L1: similar molecular structure, but different druggability profilesKatarzyna Magiera-Mularz0Justyna Kocik1Bogdan Musielak2Jacek Plewka3Dominik Sala4Monika Machula5Przemyslaw Grudnik6Malgorzata Hajduk7Marcin Czepiel8Maciej Siedlar9Tad A. Holak10Lukasz Skalniak11Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland; Corresponding authorDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandMalopolska Center of Biotechnology Jagiellonian University, Gronostajowa 7, 30-387 Krakow, PolandDepartment of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, PolandDepartment of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, PolandDepartment of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, PolandDepartment of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland; Corresponding authorSummary: In the development of PD-L1-blocking therapeutics, it is essential to transfer initial in vitro findings into proper in vivo animal models. Classical immunocompetent mice are attractive due to high accessibility and low experimental costs. However, it is unknown whether inter-species differences in PD-L1 sequence and structure would allow for human-mouse cross applications. Here, we disclose the first structure of the mouse (m) PD-L1 and analyze its similarity to the human (h) PD-L1. We show that mPD-L1 interacts with hPD-1 and provides a negative signal toward activated Jurkat T cells. We also show major differences in druggability between the hPD-L1 and mPD-L1 using therapeutic antibodies, a macrocyclic peptide, and small molecules. Our study indicates that while the amino acid sequence is well conserved between the hPD-L1 and mPD-L1 and overall structures are almost identical, crucial differences determine the interaction with anti-PD-L1 agents, that cannot be easily predicted in silico.http://www.sciencedirect.com/science/article/pii/S2589004220311573TherapeuticsImmunology |
| spellingShingle | Katarzyna Magiera-Mularz Justyna Kocik Bogdan Musielak Jacek Plewka Dominik Sala Monika Machula Przemyslaw Grudnik Malgorzata Hajduk Marcin Czepiel Maciej Siedlar Tad A. Holak Lukasz Skalniak Human and mouse PD-L1: similar molecular structure, but different druggability profiles iScience Therapeutics Immunology |
| title | Human and mouse PD-L1: similar molecular structure, but different druggability profiles |
| title_full | Human and mouse PD-L1: similar molecular structure, but different druggability profiles |
| title_fullStr | Human and mouse PD-L1: similar molecular structure, but different druggability profiles |
| title_full_unstemmed | Human and mouse PD-L1: similar molecular structure, but different druggability profiles |
| title_short | Human and mouse PD-L1: similar molecular structure, but different druggability profiles |
| title_sort | human and mouse pd l1 similar molecular structure but different druggability profiles |
| topic | Therapeutics Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220311573 |
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