6ax8
Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with methionyl-adenylateMycobacterium tuberculosis methionyl-tRNA synthetase in complex with methionyl-adenylate
Structural highlights
Function[SYM_MYCTU] Is required not only for elongation of protein synthesis but also for the initiation of all mRNA translation through initiator tRNA(fMet) aminoacylation. Publication Abstract from PubMedMycobacterium tuberculosis is a pathogenic bacterial infectious agent that is responsible for approximately 1.5 million human deaths annually. Current treatment requires the long-term administration of multiple medicines with substantial side effects. Lack of compliance, together with other factors, has resulted in a worrisome increase in resistance. New treatment options are therefore urgently needed. Here, the crystal structure of methionyl-tRNA synthetase (MetRS), an enzyme critical for protein biosynthesis and therefore a drug target, in complex with its catalytic intermediate methionyl adenylate is reported. Phenylalanine 292 of the M. tuberculosis enzyme is in an `out' conformation and barely contacts the adenine ring, in contrast to other MetRS structures where ring stacking occurs between the adenine and a protein side-chain ring in the `in' conformation. A comparison with human cytosolic MetRS reveals substantial differences in the active site as well as regarding the position of the connective peptide subdomain 1 (CP1) near the active site, which bodes well for arriving at selective inhibitors. Comparison with the human mitochondrial enzyme at the amino-acid sequence level suggests that arriving at inhibitors with higher affinity for the mycobacterial enzyme than for the mitochondrial enzyme might be achievable. The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate.,Barros-Alvarez X, Turley S, Ranade RM, Gillespie JR, Duster NA, Verlinde CLMJ, Fan E, Buckner FS, Hol WGJ Acta Crystallogr F Struct Biol Commun. 2018 Apr 1;74(Pt 4):245-254. doi:, 10.1107/S2053230X18003151. Epub 2018 Mar 28. PMID:29633973[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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