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

[摘要] 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.

[学科分类] 数学（综合）

[关键词] MYCOBACTERIUM TUBERCULOSIS;METHIONYL-TRNA SYNTHETASE;CRYSTAL STRUCTURE;INDUCED FIT;ANTITUBERCULOSIS DRUGS