Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification
Abstract
:1. Introduction
2. Results and Discussion
2.1. Mechanism of MEK1 Aberrant Activation Induced by Dehydroalanine Modification
2.1.1. Dha Modifications Mainly Affect Conformational Change of Active Segment
2.1.2. Characteristics of the Active Pocket
2.1.3. Driving Forces behind the Active Segment Conformational Changes
2.1.4. Metadynamic Simulations Indicate That Dha Modifications Cause MEK1 in a Continuous Activated State
2.2. Prediction of the Inhibitory Effects of FDA-Approved Drugs on the Catalytic Activity of Dha-Modified MEK1
2.2.1. Stability Analysis of Docking Structures
2.2.2. The Inhibitory Effect of Selumetinib on MEK1 Abnormal Activation
3. Materials and Methods
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Hydrogen Bond | WT_MEK1 | PP_MEK1 | Dha_MEK1 | |
---|---|---|---|---|
Donor | Acceptor | Occupancy | Occupancy | Occupancy |
ARG108-Side-NH1 | ASP136-Main-O | 0.25% | 24.25% | 13.75% |
ARG189-Side-NH2 | SER241-Main-O | 0.00% | 36.00% | 40.75% |
ARG189-Side-NH2 | ASP245-Side-OD1 | 0.00% | 27.00% | 26.25% |
GLY213-Main-N | TYR240-Side-OH | 0.00% | 15.00% | 48.50% |
ARG234-Side-NH2 | ASP217-Side-OD2 | 0.00% | 39.50% | 64.75% |
ARG234-Side-NE | ASP217-Side-OD1 | 0.00% | 44.75% | 73.50% |
SER244-Side-OG | GLU233-Side-OE2 | 13.25% | 23.00% | 76.50% |
ARG305-Side-NE | SER228-Side-OG | 0.00% | 0.00% | 26.00% |
Systems | Donor | Receptor | Occupancy |
---|---|---|---|
Dha_MEK1_Tra | GLU102-Side-OE2 | TRA385-Side-O33 | 27.99% |
GLU102-Side-OE1 | TRA385-Side-O33 | 21.66% | |
Dha_MEK1_Sel | ASP190-Side-OD1 | SEL385-Side-O3 | 36.98% |
MET187-Main-O | SEL385-Side-O3 | 33.33% | |
ASP190-Side-OD2 | SEL385-Side-O3 | 22.99% | |
PHE209-Main-O | SEL385-Side-O3 | 14.33% | |
MET219-Main-N | SEL385-Side-N4 | 11.33% | |
THR226-Side-OG1 | SEL 385-Side-N4 | 10.33% | |
THR226-Main-N | SEL 385-Side-F1 | 20.33% | |
ARG227-Main-N | SEL 385-Side-O3 | 20.33% | |
Dha_MEK1_Cob | PHE209-Main-N | COB385-Side-F07 | 25.61% |
ASP190-Side-OD2 | SEL385-Side-LP1 | 12.13% | |
ILE186-Side-CB | COB385-Side-LP1 | 26.33% | |
LYS185-Side-CB | COB385-Side-LP1 | 21.33% | |
GLU114-Side-CG | COB385-Side-LP1 | 11.33% | |
Dha_MEK1_Bin | ASP217-Side-OD2 | BIN385-Side-O27 | 19.93% |
ASP217-Side-OD1 | BIN385-Side-O27 | 16.61% | |
ILE216-Side-CG1 | BIN385-Side-LP1 | 12.33% | |
ASP190-Side-OD1 | BIN385-Side-O27 | 31.00% | |
ILE216-Side-CG1 | BIN385-Side-LP1 | 12.33% | |
VAL211-Side-CG2 | BIN385-Side-LP1 | 11.00% |
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Zhao, Y.; Du, S.-S.; Zhao, C.-Y.; Li, T.-L.; Tong, S.-C.; Zhao, L. Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification. Int. J. Mol. Sci. 2024, 25, 7482. https://doi.org/10.3390/ijms25137482
Zhao Y, Du S-S, Zhao C-Y, Li T-L, Tong S-C, Zhao L. Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification. International Journal of Molecular Sciences. 2024; 25(13):7482. https://doi.org/10.3390/ijms25137482
Chicago/Turabian StyleZhao, Yue, Shan-Shan Du, Chao-Yue Zhao, Tian-Long Li, Si-Cheng Tong, and Li Zhao. 2024. "Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification" International Journal of Molecular Sciences 25, no. 13: 7482. https://doi.org/10.3390/ijms25137482
APA StyleZhao, Y., Du, S. -S., Zhao, C. -Y., Li, T. -L., Tong, S. -C., & Zhao, L. (2024). Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification. International Journal of Molecular Sciences, 25(13), 7482. https://doi.org/10.3390/ijms25137482