NDLI: Structural states of the flexible catalytic loop of M. tuberculosis tyrosyl-tRNA synthetase in different enzyme

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Structural states of the flexible catalytic loop of M. tuberculosis tyrosyl-tRNA synthetase in different enzyme–substrate complexes

Content Provider	Springer Nature Link
Author	Mykuliak, Vasyl V. Dragan, Anatoliy I. Kornelyuk, Alexander I.
Copyright Year	2014
Abstract	Tyrosyl-tRNA synthetase from Mycobacterium tuberculosis (MtTyrRS) is an enzyme that belongs to class I of aminoacyl-tRNA synthetases, which catalyze the attachment of l-tyrosine to its cognate tRNATyr in the preribosomal step of protein synthesis. MtTyrRS is incapable of cross-recognition and aminoacylation of human cytoplasmic tRNATyr, so this enzyme may be a promising target for development of novel selective inhibitors as putative antituberculosis drugs. As a class I aminoacyl-tRNA synthetase, MtTyrRS contains the HIGH-like and KFGKS catalytic motifs that catalyze amino acid activation with ATP. In this study, the conformational mobility of MtTyrRS catalytic KFGKS loop was analyzed by 100-ns all-atoms molecular dynamics simulations of the free enzyme and its complexes with different substrates: tyrosine, ATP, and the tyrosyl–adenylate intermediate. It was shown that in the closed state of the active site, the KFGKS loop, readily adopts different stable conformations depending on the type of bound substrate. Molecular dynamics simulations revealed that the closed state of the loop is stabilized by dynamic formation of two antiparallel β-sheets at flanking ends which hold the KFGKS fragment inside the active center. Prevention of β-sheet formation by introducing point mutations in the loop sequence results in a rapid (<20 ns) transition of the loop from its functional “closed” M-like structure to an inactive “open” O-like structure, i.e. rapid diffusion of the catalytic loop outside the active site. The flexibility and rapid dynamics of the wild-type aaRS catalytic loop structure are crucial for formation of protein–substrate interactions and subsequently for overall enzyme functional activity.
Starting Page	613
Ending Page	622
Page Count	10
File Format	PDF
ISSN	01757571
Journal	European Biophysics Journal
Volume Number	43
Issue Number	12
e-ISSN	14321017
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2014-11-06
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Tyrosyl-tRNA synthetase Mycobacterium tuberculosis Active site Molecular dynamics β-strands Grid technology Biochemistry Biophysics and Biological Physics Cell Biology Neurobiology Membrane Biology Nanotechnology
Content Type	Text
Resource Type	Article
Subject	Medicine Biophysics

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