Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study
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...
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PeerJ Inc.
2019-01-01
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| author | Yan Han Yungang Wu Yi Xu Wentao Guo Na Zhang Xiaoyi Wang |
| author_facet | Yan Han Yungang Wu Yi Xu Wentao Guo Na Zhang Xiaoyi Wang |
| author_sort | Yan Han |
| collection | DOAJ |
| description | 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. |
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| last_indexed | 2024-03-09T06:56:59Z |
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| spelling | doaj.art-438e3dee9b0748c5b85cc8a23c30d8822023-12-03T10:02:45ZengPeerJ Inc.PeerJ2167-83592019-01-017e629910.7717/peerj.6299Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling studyYan Han0Yungang Wu1Yi Xu2Wentao Guo3Na Zhang4Xiaoyi Wang5Department of TCM Orthopedics & Traumatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of TCM Orthopedics & Traumatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of Pharmacy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaSchool of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of TCM Orthopedics & Traumatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaDepartment of TCM Orthopedics & Traumatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, ChinaBackground 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.https://peerj.com/articles/6299.pdfMutationMonopolar spindle 1Resistance mechanismMolecular dynamics simulation |
| spellingShingle | Yan Han Yungang Wu Yi Xu Wentao Guo Na Zhang Xiaoyi Wang Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study PeerJ Mutation Monopolar spindle 1 Resistance mechanism Molecular dynamics simulation |
| title | Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study |
| title_full | Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study |
| title_fullStr | Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study |
| title_full_unstemmed | Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study |
| title_short | Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study |
| title_sort | molecular mechanism of point mutation induced monopolar spindle 1 mps1 ttk inhibitor resistance revealed by a comprehensive molecular modeling study |
| topic | Mutation Monopolar spindle 1 Resistance mechanism Molecular dynamics simulation |
| url | https://peerj.com/articles/6299.pdf |
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