Comparative structural dynamics of Tyrosyl-tRNA synthetase complexed with different substrates explored by molecular dynamics |
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Authors: | Tong Li Matheus Froeyen Piet Herdewijn |
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Institution: | (1) Laboratory for Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium |
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Abstract: | Several molecular dynamics simulations of S. aureus Tyrosyl-tRNA synthetase (TyrRS) in its free form and complexed with Tyr, ATP, tyrosyl adenylate and inhibitor respectively
have been carried out to investigate the ligand-linked conformational stability changes associated with its catalytic cycle.
The results show that unliganded S. aureus TyrRS samples a more relaxed conformational space than substrate-bound TyrRS. There are three high flexibility regions encompassing
residues 114–118, 128–133, and 226–238 respectively. The region which includes the KMSKS motif (KFGKS in S. aureus TyrRS) shows the highest difference in fluctuations. Hydrogen bond network formed by Tyr, ATP, tyrosyl adenylate and inhibitor
with S. aureus TyrRS is discussed. Our simulations suggest the induced-fit conformational changes of the KMSKS loop as follows: the KMSKS
loop of substrate-free S. aureus TyrRS adopts an open conformation. The tyrosine binds in the pocket with the KMSKS loop balancing between semi-open and open
forms. The ATP binding induces the KMSKS loop to the open form. After the Tyr-AMP is formed, the first two residues of KMSKS
loop twists in an anticlockwise direction and drives the loop in a conformation similar to the closed one, while those of
the last three GKS residues adopt a conformation between semi-open and open conformation. This conformational change may probably
be involved in the initial tRNA binding.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Tyrosyl-tRNA synthetase Aminoacyl-tRNA synthetases KMSKS Molecular dynamics Hydrogen bond |
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