Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib
The kinase domain is highly conserved among protein kinases 'in terms of both sequence and structure. Conformational rearrangements of the kinase domain are affected by the phosphorylation of residues and the binding of kinase inhibitors. Interestingly, the conformational rearrangement of the a...
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022001933 |
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| author | Mingsong Shi Lun Wang Kongjun Liu Yong Chen Mengshi Hu Linyu Yang Jun He Lijuan Chen Dingguo Xu |
| author_facet | Mingsong Shi Lun Wang Kongjun Liu Yong Chen Mengshi Hu Linyu Yang Jun He Lijuan Chen Dingguo Xu |
| author_sort | Mingsong Shi |
| collection | DOAJ |
| description | The kinase domain is highly conserved among protein kinases 'in terms of both sequence and structure. Conformational rearrangements of the kinase domain are affected by the phosphorylation of residues and the binding of kinase inhibitors. Interestingly, the conformational rearrangement of the active pocket plays an important role in kinase activity and can be used to design novel kinase inhibitors. We characterized the conformational plasticity of the active pocket when bosutinib was bound to salt-inducible kinase 2 (SIK2) using homology modeling and molecular dynamics simulations. Ten different initial complex models were constructed using the Morph server, ranging from open to closed conformations of SIK2 binding with bosutinib. Our simulation showed that bosutinib binds SIK2 with up or down conformations of the P-loop and with all the conformations of the activation loop. In addition, the αC-helix conformation was induced by the conformation of the activation loop, and the salt bridge formed only with its open conformation. The binding affinity of the models was also determined using the molecular mechanics generalized Born surface area method. Bosutinib was found to form a strong binding model with SIK2 and hydrophobic interactions were the dominant factor. This discovery may help guide the design of novel SIK2 inhibitors. |
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| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:20:06Z |
| publishDate | 2022-01-01 |
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| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-f44f140e00d745749987bda52374934d2022-12-24T04:52:38ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012025742586Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinibMingsong Shi0Lun Wang1Kongjun Liu2Yong Chen3Mengshi Hu4Linyu Yang5Jun He6Lijuan Chen7Dingguo Xu8State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Corresponding authors.College of Chemistry, MOE Key Laboratory of Green Chemistry and Technology, Sichuan University, Chengdu, Sichuan 610064, China; Research Center for Material Genome Engineering, Sichuan University, Chengdu, Sichuan 610065, China; Corresponding authors.The kinase domain is highly conserved among protein kinases 'in terms of both sequence and structure. Conformational rearrangements of the kinase domain are affected by the phosphorylation of residues and the binding of kinase inhibitors. Interestingly, the conformational rearrangement of the active pocket plays an important role in kinase activity and can be used to design novel kinase inhibitors. We characterized the conformational plasticity of the active pocket when bosutinib was bound to salt-inducible kinase 2 (SIK2) using homology modeling and molecular dynamics simulations. Ten different initial complex models were constructed using the Morph server, ranging from open to closed conformations of SIK2 binding with bosutinib. Our simulation showed that bosutinib binds SIK2 with up or down conformations of the P-loop and with all the conformations of the activation loop. In addition, the αC-helix conformation was induced by the conformation of the activation loop, and the salt bridge formed only with its open conformation. The binding affinity of the models was also determined using the molecular mechanics generalized Born surface area method. Bosutinib was found to form a strong binding model with SIK2 and hydrophobic interactions were the dominant factor. This discovery may help guide the design of novel SIK2 inhibitors.http://www.sciencedirect.com/science/article/pii/S2001037022001933Conformational diversitiesActive pocketSalt-inducible kinase 2BosutinibMolecular dynamics simulation |
| spellingShingle | Mingsong Shi Lun Wang Kongjun Liu Yong Chen Mengshi Hu Linyu Yang Jun He Lijuan Chen Dingguo Xu Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib Computational and Structural Biotechnology Journal Conformational diversities Active pocket Salt-inducible kinase 2 Bosutinib Molecular dynamics simulation |
| title | Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib |
| title_full | Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib |
| title_fullStr | Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib |
| title_full_unstemmed | Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib |
| title_short | Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib |
| title_sort | molecular dynamics simulations of the conformational plasticity in the active pocket of salt inducible kinase 2 sik2 multi state binding with bosutinib |
| topic | Conformational diversities Active pocket Salt-inducible kinase 2 Bosutinib Molecular dynamics simulation |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022001933 |
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