Structural characterization of free-state and product-state Mycobacterium tuberculosis methionyl-tRNA synthetase reveals an induced-fit ligand-recognition mechanism

IUCrJ
Wei WangSheng Cui

Abstract

Mycobacterium tuberculosis (MTB) caused 10.4 million cases of tuberculosis and 1.7 million deaths in 2016. The incidence of multidrug-resistant and extensively drug-resistant MTB is becoming an increasing threat to public health and the development of novel anti-MTB drugs is urgently needed. Methionyl-tRNA synthetase (MetRS) is considered to be a valuable drug target. However, structural characterization of M. tuberculosis MetRS (MtMetRS) was lacking for decades, thus hampering drug design. Here, two high-resolution crystal structures of MtMetRS are reported: the free-state structure (apo form; 1.9 Å resolution) and a structure with the intermediate product methionyl-adenylate (Met-AMP) bound (2.4 Å resolution). It was found that free-state MtMetRS adopts a previously unseen conformation that has never been observed in other MetRS homologues. The pockets for methionine and AMP are not formed in free-state MtMetRS, suggesting that it is in a nonproductive conformation. Combining these findings suggests that MtMetRS employs an induced-fit mechanism in ligand binding. By comparison with the structure of human cytosolic MetRS, additional pockets specific to MtMetRS that could be used for anti-MTB drug design were located.

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Citations

Nov 7, 2019·Journal of Computer-aided Molecular Design·Galyna P VolynetsMichail A Tukalo
Feb 14, 2021·International Journal of Molecular Sciences·Luping PangArthur Van Aerschot
Dec 15, 2020·Biophysics Reviews·Enrico Di Cera
Apr 16, 2021·The Journal of Biological Chemistry·Gustavo Fernando MercaldiCelso Eduardo Benedetti

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Methods Mentioned

BETA
PCR
gel-filtration
thermal shift
size-exclusion chromatography
co-crystallization
thermal shifts
PISA

Software Mentioned

CASTp
DALI
PHENIX
XDS
CFX Manager
Coot
PyMOL
MtMerRS

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