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Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a
Yan Han1, Yungang Wu1, Yi Xu2
1Department of TCM Orthopedics & Traumatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Background:
Monopolar spindle 1 (Mps1/TTK) is an apical dual-specificity protein kinase in the spindle assembly checkpoint (SAC) that guarantees accurate segregation of chromosomes during mitosis. High levels of Mps1 are found in various types of human malignancies, such as glioblastoma, osteosarcoma, hepatocellular carcinoma, and breast cancer. Several potent inhibitors of Mps1 exist, and exhibit promising activity in many cell cultures and xenograft models. However, resistance due to point mutations in the kinase domain of Mps1 limits the therapeutic effects of these inhibitors. Understanding the detailed resistance mechanism induced by Mps1 point mutations is therefore vital for the development of novel inhibitors against malignancies.
Methods:
In this study, conventional molecular dynamics (MD) simulation and Gaussian accelerated MD (GaMD) simulation were performed to elucidate the resistance mechanisms of Cpd-5, a potent Mps1 inhibitor, induced by the four representative mutations I531M, I598F, C604Y, S611R.
Results:
Our results from conventional MD simulation combined with structural analysis and free energy calculation indicated that the four mutations weaken the binding affinity of Cpd-5 and the major variations in structural were the conformational changes of the P-loop, A-loop and αC-helix. Energetic differences of per-residue between the WT system and the mutant systems indicated the mutations may allosterically regulate the conformational ensemble and the major variations were residues of Ile-663 and Gln-683, which located in the key loops of catalytic loop and A-loop, respectively. The large conformational and energetic differences were further supported by the GaMD simulations. Overall, these obtained molecular mechanisms will aid rational design of novel Mps1 inhibitors to combat inhibitor resistance.
Insights
Point mutations in Mps1 (Monopolar spindle 1) can cause resistance to cancer inhibitors. Molecular dynamics simulations revealed how these mutations alter Mps1 structure, affecting inhibitor binding and guiding the development of new drugs.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Structural Biology
Background:
- Monopolar spindle 1 (Mps1/TTK) is crucial for accurate chromosome segregation during mitosis.
- Elevated Mps1 levels are linked to various human cancers, making it a therapeutic target.
- Mps1 inhibitors show promise but face resistance due to kinase domain mutations.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying resistance to the Mps1 inhibitor Cpd-5 caused by specific point mutations.
- To understand how these mutations affect Mps1 structure and inhibitor binding affinity.
Main Methods:
- Conventional molecular dynamics (MD) simulations were employed.
- Gaussian accelerated MD (GaMD) simulations were used to further investigate conformational changes.
- Structural analysis and free energy calculations were performed on four representative Mps1 mutations (I531M, I598F, C604Y, S611R).
Main Results:
- The four studied mutations significantly weaken the binding affinity of the Mps1 inhibitor Cpd-5.
- Key structural alterations include conformational changes in the P-loop, A-loop, and αC-helix.
- Mutations were found to allosterically regulate the conformational ensemble, particularly affecting residues Ile-663 and Gln-683.
Conclusions:
- Detailed molecular mechanisms of Mps1 inhibitor resistance have been identified.
- These findings provide a basis for the rational design of novel Mps1 inhibitors to overcome resistance.
- Understanding resistance mechanisms is vital for developing effective cancer therapies targeting Mps1.
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