The crystal structure of the drug target Mycobacterium tuberculosis methionyl-tRNA synthetase in complex with a catalytic intermediate
| Autor: | Ximena Barros-Álvarez, Wim G. J. Hol, Christophe L. M. J. Verlinde, Stewart Turley, Frederick S. Buckner, Erkang Fan, Ranae M. Ranade, Nicole A. Duster, J. Robert Gillespie |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Protein Conformation Biophysics Peptide Methionine-tRNA Ligase Crystallography X-Ray Biochemistry Catalysis Research Communications Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Structural Biology Catalytic Domain Genetics Protein biosynthesis chemistry.chemical_classification DNA ligase biology Aminoacyl tRNA synthetase Active site Condensed Matter Physics biology.organism_classification 030104 developmental biology Enzyme chemistry Drug Design biology.protein Crystallization Mycobacterium Protein Binding |
| Zdroj: | Acta crystallographica. Section F, Structural biology communications. 74(Pt 4) |
| ISSN: | 2053-230X |
| Popis: | Mycobacterium tuberculosisis 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 theM. tuberculosisenzyme 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. |
| Databáze: | OpenAIRE |
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