6AX8
Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with methionyl-adenylate
Summary for 6AX8
| Entry DOI | 10.2210/pdb6ax8/pdb |
| Descriptor | Methionine-tRNA ligase, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-oxolan-2-yl]methoxy-hydroxy-phosphoryl] (2S)-2-azanyl-4-methylsulfanyl-butanoate (3 entities in total) |
| Functional Keywords | synthetase, ligase, ligase-aminoacyl adenylate complex |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 58636.82 |
| Authors | Barros-Alvarez, X.,Hol, W.G.J. (deposition date: 2017-09-06, release date: 2018-04-11, Last modification date: 2024-03-13) |
| Primary citation | Barros-Alvarez, X.,Turley, S.,Ranade, R.M.,Gillespie, J.R.,Duster, N.A.,Verlinde, C.L.M.J.,Fan, E.,Buckner, F.S.,Hol, W.G.J. The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate. Acta Crystallogr F Struct Biol Commun, 74:245-254, 2018 Cited by PubMed 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. PubMed: 29633973DOI: 10.1107/S2053230X18003151 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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