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The molecular mechanism behind protein kinase B natural mutant E17K affecting the allosteric inhibitor sensitivity: a

Yan Wang1, Ran Jia2, Wen Tan1

  • 1Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, People's Republic of China.

Journal of Biomolecular Structure & Dynamics
|May 27, 2020
PubMed

Insights

The Akt1 E17K mutation, linked to cancers, alters allosteric inhibitor sensitivity by disrupting key residue interactions. This finding aids in designing targeted therapies for Akt1 mutants.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • Akt1 is implicated in numerous human cancers.
  • Natural variants like Glu17Lys (E17K) can influence drug efficacy.
  • Allosteric inhibitors targeting Akt1 are crucial in cancer therapy.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the Akt1 E17K mutation affects allosteric inhibitor sensitivity.
  • To provide a structural basis for understanding altered drug response in cancer mutants.

Main Methods:

  • Molecular dynamics simulations were employed for both wild-type Akt1 and the E17K mutant.
  • Analysis included structural stability, hydrogen bonding, pi-pi interactions, and binding free energy.
  • Key residue interactions at the allosteric binding site were investigated.

Main Results:

  • The E17K substitution significantly impacts the interaction between residue K297 and allosteric inhibitors.
  • This disruption leads to the dissociation of allosteric inhibitors from the binding site in the E17K mutant.
  • Structural stability and binding affinities were altered compared to wild-type Akt1.

Conclusions:

  • The Akt1 E17K mutation confers resistance to certain allosteric inhibitors by altering critical binding interactions.
  • These findings offer a theoretical foundation for developing next-generation allosteric inhibitors tailored for E17K Akt1 mutants.
  • Understanding these molecular mechanisms is vital for personalized cancer treatment strategies.
Keywords:
Molecular dynamics simulationallosteric inhibitorsbinding free energy calculationsprotein kinase Bπ – π interactions

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