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

Wang W, Qin B, Wojdyla JA, Wang M, Gao X, Cui S
IUCrJ 5 478-490 (2018)
Cited: 9 times
EuropePMC logo PMID: 30002848

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.

Articles - 5xet mentioned but not cited (1)

  1. Structural characterization of free-state and product-state Mycobacterium tuberculosis methionyl-tRNA synthetase reveals an induced-fit ligand-recognition mechanism. Wang W, Qin B, Wojdyla JA, Wang M, Gao X, Cui S. IUCrJ 5 478-490 (2018)


Reviews citing this publication (2)

  1. Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery. Pang L, Weeks SD, Van Aerschot A. Int J Mol Sci 22 1750 (2021)
  2. Mechanisms of ligand binding. Di Cera E. Biophys Rev (Melville) 1 011303 (2020)

Articles citing this publication (6)

  1. Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among N-benzylidene-N'-thiazol-2-yl-hydrazines. Kovalenko OP, Volynets GP, Rybak MY, Starosyla SA, Gudzera OI, Lukashov SS, Bdzhola VG, Yarmoluk SM, Boshoff HI, Tukalo MA. Medchemcomm 10 2161-2169 (2019)
  2. High methionyl-tRNA synthetase expression predicts poor prognosis in patients with breast cancer. Jin Q, Liu G, Wang B, Li S, Ni K, Wang C, Ren J, Zhang S, Dai Y. J Clin Pathol 73 803-812 (2020)
  3. Dual-targeted hit identification using pharmacophore screening. Volynets GP, Starosyla SA, Rybak MY, Bdzhola VG, Kovalenko OP, Vdovin VS, Yarmoluk SM, Tukalo MA. J Comput Aided Mol Des 33 955-964 (2019)
  4. Molecular basis for diaryldiamine selectivity and competition with tRNA in a type 2 methionyl-tRNA synthetase from a Gram-negative bacterium. Mercaldi GF, Andrade MO, Zanella JL, Cordeiro AT, Benedetti CE. J Biol Chem 296 100658 (2021)
  5. Computational Insight into Substrate-Induced Conformational Changes in Methionyl-tRNA Synthetase of Mycobacterium Tuberculosis. Thakur S, Mehra R. Protein J 42 533-546 (2023)
  6. Discovery of novel antituberculosis agents among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives targeting aminoacyl-tRNA synthetases. Rybak MY, Balanda AO, Yatsyshyna AP, Kotey IM, Starosyla SA, Bdzhola VG, Lukash LL, Yarmoluk SM, Tukalo MA, Volynets GP. Sci Rep 11 7162 (2021)


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