Abstract
BackgroundMonopolar 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.MethodsIn 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.ResultsOur 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.
Highlights
Mammalian cell division is accurately regulated by activation and inactivation of related proteins that manage progression through the phases of the cell cycle (Bertoli, Skotheim & De Bruin, 2013)
The structural dynamics of Cpd-5 bound with wild type (WT) Mps1 or mutant Mps1 were analyzed by performing 240 ns conventional molecular dynamics (MD) simulations
The average root mean square deviation (RMSD) values of both the Mps1 protein and the Cpd-5 follow the order of WT systems
Summary
Mammalian cell division is accurately regulated by activation and inactivation of related proteins that manage progression through the phases of the cell cycle (Bertoli, Skotheim & De Bruin, 2013). Reduction in Mps levels or activity in these tumors can lead to loss of cell viability; inhibition of Mps has been regard as an attractive strategy to target cancers, especially those with chromosomal instability (Daniel et al, 2011; Xie et al, 2017). Conventional molecular dynamics (MD) simulation and Gaussian accelerated MD (GaMD) simulation were performed to elucidate the resistance mechanisms of Cpd-5, a potent Mps inhibitor, induced by the four representative mutations I531M, I598F, C604Y, S611R. The large conformational and energetic differences were further supported by the GaMD simulations Overall, these obtained molecular mechanisms will aid rational design of novel Mps inhibitors to combat inhibitor resistance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
