1. The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate.
- Author
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Barros-Álvarez X, Turley S, Ranade RM, Gillespie JR, Duster NA, Verlinde CLMJ, Fan E, Buckner FS, and Hol WGJ
- Subjects
- Catalysis, Catalytic Domain, Crystallization, Crystallography, X-Ray, Models, Molecular, Protein Binding, Protein Conformation, Drug Design, Methionine-tRNA Ligase chemistry, Methionine-tRNA Ligase metabolism, Mycobacterium tuberculosis enzymology
- Abstract
Mycobacterium 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.
- Published
- 2018
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