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Reduced efficacy of a Src kinase inhibitor in crowded protein solution
The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253829/ https://www.ncbi.nlm.nih.gov/pubmed/34215742 http://dx.doi.org/10.1038/s41467-021-24349-5 |
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author | Kasahara, Kento Re, Suyong Nawrocki, Grzegorz Oshima, Hiraku Mishima-Tsumagari, Chiemi Miyata-Yabuki, Yukako Kukimoto-Niino, Mutsuko Yu, Isseki Shirouzu, Mikako Feig, Michael Sugita, Yuji |
author_facet | Kasahara, Kento Re, Suyong Nawrocki, Grzegorz Oshima, Hiraku Mishima-Tsumagari, Chiemi Miyata-Yabuki, Yukako Kukimoto-Niino, Mutsuko Yu, Isseki Shirouzu, Mikako Feig, Michael Sugita, Yuji |
author_sort | Kasahara, Kento |
collection | PubMed |
description | The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, 4-amino-5-(4-methylphenyl)−7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. |
format | Online Article Text |
id | pubmed-8253829 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82538292021-07-20 Reduced efficacy of a Src kinase inhibitor in crowded protein solution Kasahara, Kento Re, Suyong Nawrocki, Grzegorz Oshima, Hiraku Mishima-Tsumagari, Chiemi Miyata-Yabuki, Yukako Kukimoto-Niino, Mutsuko Yu, Isseki Shirouzu, Mikako Feig, Michael Sugita, Yuji Nat Commun Article The inside of a cell is highly crowded with proteins and other biomolecules. How proteins express their specific functions together with many off-target proteins in crowded cellular environments is largely unknown. Here, we investigate an inhibitor binding with c-Src kinase using atomistic molecular dynamics (MD) simulations in dilute as well as crowded protein solution. The populations of the inhibitor, 4-amino-5-(4-methylphenyl)−7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), in bulk solution and on the surface of c-Src kinase are reduced as the concentration of crowder bovine serum albumins (BSAs) increases. This observation is consistent with the reduced PP1 inhibitor efficacy in experimental c-Src kinase assays in addition with BSAs. The crowded environment changes the major binding pathway of PP1 toward c-Src kinase compared to that in dilute solution. This change is explained based on the population shift mechanism of local conformations near the inhibitor binding site in c-Src kinase. Nature Publishing Group UK 2021-07-02 /pmc/articles/PMC8253829/ /pubmed/34215742 http://dx.doi.org/10.1038/s41467-021-24349-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kasahara, Kento Re, Suyong Nawrocki, Grzegorz Oshima, Hiraku Mishima-Tsumagari, Chiemi Miyata-Yabuki, Yukako Kukimoto-Niino, Mutsuko Yu, Isseki Shirouzu, Mikako Feig, Michael Sugita, Yuji Reduced efficacy of a Src kinase inhibitor in crowded protein solution |
title | Reduced efficacy of a Src kinase inhibitor in crowded protein solution |
title_full | Reduced efficacy of a Src kinase inhibitor in crowded protein solution |
title_fullStr | Reduced efficacy of a Src kinase inhibitor in crowded protein solution |
title_full_unstemmed | Reduced efficacy of a Src kinase inhibitor in crowded protein solution |
title_short | Reduced efficacy of a Src kinase inhibitor in crowded protein solution |
title_sort | reduced efficacy of a src kinase inhibitor in crowded protein solution |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253829/ https://www.ncbi.nlm.nih.gov/pubmed/34215742 http://dx.doi.org/10.1038/s41467-021-24349-5 |
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