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Computational dissection of allosteric inhibition of the SH2 domain of Bcr-Abl kinase by the monobody inhibitor AS25

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Abstract

The deregulated breakpoint cluster region (Bcr)–Abelson tyrosine kinase (Abl) fusion protein represents an attractive pharmacological target for the treatment of chronic myeloid leukemia (CML). The high affinity of monobody AS25 was designed to target the Src homology 2 (SH2) domain of Bcr-Abl, leading to allosteric inhibition of Bcr-Abl through formation of protein–protein interactions. An I164E mutation in the SH2 domain disrupts AS25 binding to the SH2 domain of Bcr-Abl. The detailed mechanisms, however, remain to be unresolved. Here, molecular dynamics (MD) simulations and binding free energy calculations were performed to explore the conformational and energetic differences between the wild-type (WT) complexes of Bcr-Abl SH2 domain and AS25 (SH2WT–AS25) as well as the mutated complexes (SH2I164E–AS25). The results revealed that I164E mutation not only caused an increase in the conformational flexibility of SH2–AS25 complexes, but also weakened the binding affinity of AS25 to SH2. The comparative binding modes of SH2-AS25 complexes between WT and the I164E mutant were comprehensively analyzed to unravel the disruption of hydrophobic and hydrogen bonding interactions in the interface of the SH2-AS25 complex triggered by the I164E mutation. The results obtained may help to design the next generation of higher affinity Bcr-Abl SH2-specific peptide inhibitors.

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Acknowledgment

The authors thank the high performance supercomputer center at Shanghai.

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Authors and Affiliations

  1. Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China

    Mingfei Ji, Zhongqin Zhang & Guanqun Jv

  2. Department of VIP Clinic, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Guodong Zheng & Jialin Wang

  3. Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Xiaolong Li

  4. Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China

    Xiaowei Wang

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  1. Mingfei Ji
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  2. Guodong Zheng
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  3. Xiaolong Li
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  4. Zhongqin Zhang
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  5. Guanqun Jv
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  6. Xiaowei Wang
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  7. Jialin Wang
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Correspondence to Xiaowei Wang or Jialin Wang.

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Funding

This work was supported by Shanghai Health and Family Planning Commission (20154Y0058).

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The authors declare that they have no conflict of interest.

Additional information

Mingfei Ji, Guodong Zheng, and Xiaolong Li wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors

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Ji, M., Zheng, G., Li, X. et al. Computational dissection of allosteric inhibition of the SH2 domain of Bcr-Abl kinase by the monobody inhibitor AS25. J Mol Model 23, 183 (2017). https://doi.org/10.1007/s00894-017-3353-5

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  • DOI: https://doi.org/10.1007/s00894-017-3353-5

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