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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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