Nature of Irreversible Inhibition of Human 20S Proteasome by Salinosporamide A. The Critical Role of Lys–Asp Dyad Revealed from Electrostatic Effects Analysis
| Autor: | Vicent Moliner, Katarzyna Świderek, Natalia Serrano-Aparicio |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
010405 organic chemistry salinosporamide A General Chemistry 010402 general chemistry QM/MM 01 natural sciences 20s proteasome Catalysis anticancer natural products 0104 chemical sciences Cell biology Cellular protein covalent inhibition 20S proteasome chemistry.chemical_compound electrostatic potential Enzyme chemistry inhibition mechanism Salinosporamide A free energy surfaces |
| Zdroj: | ACS Catalysis. 11:3575-3589 |
| ISSN: | 2155-5435 |
| DOI: | 10.1021/acscatal.0c05313 |
| Popis: | 20S proteasome is the enzymatic core engine involved in the processes of cellular protein regulation, thus becoming a promising target inter alia in the therapy of many diseases. In this work, the mechanism of the irreversible inhibition of the β5 subunit of human 20S proteasome by salinosporamide A (SalA) was studied by means of QM/MM molecular dynamics simulations. The free energy landscape computed at the M06-2X:AM1/AMBER level reveals the existence of a favorable pathway, where Lys33 actively participates in the inhibition process. This mechanism that presents a free energy barrier for the rate-limiting step in agreement with the experimentally measured rate constant is different from the widely accepted SalA-assisted mechanism. Analysis of the electrostatic features of 20S proteasome reveals the importance of the electrostatic preorganization/reorganization of the enzyme and the pivotal role of Asp17 in modulating pKa of Lys33 and explains how a molecule, completely unlike the natural substrate of 20S proteasome, binds and inhibits its active site. Our results can contribute to the refinement of efficient inhibitors of a key player in the cell protein quality control system, with the consequent potential applications in medical treatments. |
| Databáze: | OpenAIRE |
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