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- Title
The crystal structure of the drug target <italic>Mycobacterium tuberculosis</italic> methionyl‐tRNA synthetase in complex with a catalytic intermediate.
- Authors
Barros-Álvarez, Ximena; Turley, Stewart; Ranade, Ranae M.; Gillespie, J. Robert; Duster, Nicole A.; Verlinde, Christophe L. M. J.; Fan, Erkang; Buckner, Frederick S.; Hol, Wim G. J.
- Abstract
<italic>Mycobacterium tuberculosis</italic> 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 <italic>M. tuberculosis</italic> 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.
- Subjects
MYCOBACTERIUM tuberculosis; CRYSTAL structure; LIGASES
- Publication
Acta Crystallographica: Section F, Structural Biology Communications, 2018, Vol 74, Issue 4, p245
- ISSN
2053-230X
- Publication type
Article
- DOI
10.1107/S2053230X18003151