Comparative structural dynamics of Tyrosyl-tRNA synthetase complexed with different substrates explored by molecular...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Staphylococcus aureus Tyrosyl-tRNA synthetase (TyrRS) is crucial for protein synthesis.
• Understanding TyrRS conformational dynamics is key to its catalytic mechanism and potential drug targeting.

Purpose of the Study:

• To investigate ligand-induced conformational stability changes in S. aureus TyrRS during its catalytic cycle.
• To elucidate the role of the KMSKS loop in TyrRS function and substrate binding.

Main Methods:

• Molecular dynamics simulations of S. aureus TyrRS in various ligand-bound states (free, Tyr, ATP, tyrosyl adenylate, inhibitor).
• Analysis of residue fluctuations and hydrogen bond networks to identify flexible regions and interactions.

Main Results:

• Unliganded TyrRS exhibits a more relaxed conformational space compared to substrate-bound forms.
• High flexibility regions identified, with the KMSKS motif (KFGKS) showing the most significant fluctuation differences.
• Distinct KMSKS loop conformations observed: open in substrate-free, balancing in tyrosine-bound, open in ATP-bound, and transitioning towards closed upon Tyr-AMP formation.

Conclusions:

• Ligand binding, especially ATP, induces specific conformational changes in the KMSKS loop of S. aureus TyrRS.
• These induced-fit movements of the KMSKS loop are likely involved in the initial binding of tRNA, suggesting a regulatory role in the synthetase's catalytic cycle.