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Molecular Dynamics Simulations of A27S and K120A Mutated PTP1B Reveals Selective Binding of the Bidentate Inhibitor
Xi Chen1, Xia Liu2, Qiang Gan1
1State Key Laboratory of Explosion Science and Technology, Beijing Institute of Technology, No. 5, Zhongguancun South Street, Haidian District, Beijing 100081, China.
Abstract:
Protein tyrosine phosphatase 1B (PTP1B) is considered a potential target for the treatment of type II diabetes and obesity due to its critical negative role in the insulin signaling pathway. However, improving the selectivity of PTP1B inhibitors over the most closely related T-cell protein tyrosine phosphatase (TCPTP) remains a major challenge for inhibitor development. Lys120 at the active site and Ser27 at the second pTyr binding site are distinct in PTP1B and TCPTP, which may bring differences in binding affinity. To explore the determinant of selective binding of inhibitor, molecular dynamics simulations with binding free energy calculations were performed on K120A and A27S mutated PTP1B, and the internal changes induced by mutations were investigated. Results reveal that the presence of Lys120 induces a conformational change in the WPD-loop and YRD-motif and has a certain effect on the selective binding at the active site. Ser27 weakens the stability of the inhibitor at the second pTyr binding site by altering the orientation of the Arg24 and Arg254 side chains via hydrogen bonds. Further comparison of alanine scanning demonstrates that the reduction in the energy contribution of Arg254 caused by A27S mutation leads to a different inhibitory activity. These observations provide novel insights into the selective binding mechanism of PTP1B inhibitors to TCPTP.
Insights
Understanding protein tyrosine phosphatase 1B (PTP1B) selectivity is key for developing diabetes and obesity treatments. Mutations reveal how Lys120 and Ser27 influence inhibitor binding, guiding future drug design.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Protein tyrosine phosphatase 1B (PTP1B) is a crucial negative regulator of insulin signaling, making it a therapeutic target for type II diabetes and obesity.
- Achieving selective inhibition of PTP1B over the highly similar T-cell protein tyrosine phosphatase (TCPTP) is a significant challenge in drug development.
Purpose of the Study:
- To investigate the molecular determinants responsible for the selective binding of PTP1B inhibitors.
- To elucidate the impact of key residues Lys120 and Ser27 on inhibitor binding affinity and selectivity between PTP1B and TCPTP.
Main Methods:
- Molecular dynamics simulations were employed to study wild-type and mutated (K120A, A27S) PTP1B.
- Binding free energy calculations and alanine scanning were performed to assess the energetic contributions of specific residues.
Main Results:
- Lysine 120 (Lys120) at the active site influences PTP1B conformation, affecting selective binding.
- Serine 27 (Ser27) at the second pTyr binding site impacts inhibitor stability by altering hydrogen bonding networks involving Arg24 and Arg254.
- The A27S mutation reduces the energy contribution of Arg254, leading to altered inhibitory activity.
Conclusions:
- Distinct residues Lys120 and Ser27 play critical roles in the differential binding of inhibitors to PTP1B and TCPTP.
- These findings provide valuable insights into the mechanism of selective PTP1B inhibition, aiding the design of more effective therapeutics for metabolic disorders.
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