Reduced efficacy of a Src kinase inhibitor in crowded protein solution

Kento Kasahara, Suyong Re, Grzegorz Nawrocki, Hiraku Oshima, Chiemi Mishima-Tsumagari, Yukako Miyata-Yabuki, Mutsuko Kukimoto-Niino, Isseki Yu, Mikako Shirouzu, Michael Feig () and Yuji Sugita ()
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Kento Kasahara: Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research
Suyong Re: Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research
Grzegorz Nawrocki: Michigan State University
Hiraku Oshima: Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research
Chiemi Mishima-Tsumagari: Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research
Yukako Miyata-Yabuki: Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research
Mutsuko Kukimoto-Niino: Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research
Isseki Yu: Maebashi Institute of Technology, Kamisadori-machi, Maebashi
Mikako Shirouzu: Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research
Michael Feig: Michigan State University
Yuji Sugita: Laboratory for Biomolecular Function Simulation, RIKEN Center for Biosystems Dynamics Research

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24349-5

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