6AX8

Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with methionyl-adenylate

6AX8 の概要

• エントリーDOI: 10.2210/pdb6ax8/pdb
• 分子名称: 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)
• 機能のキーワード: synthetase, ligase, ligase-aminoacyl adenylate complex
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58636.82

構造登録者

Barros-Alvarez, X.,Hol, W.G.J. (登録日: 2017-09-06, 公開日: 2018-04-11, 最終更新日: 2024-03-13)

主引用文献

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

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: 29633973
DOI: 10.1107/S2053230X18003151

実験手法

X-RAY DIFFRACTION (2.6 Å)