Distinct states of methionyl-tRNA synthetase indicate inhibitor binding by conformational selection.
Structure
; 20(10): 1681-91, 2012 Oct 10.
Article
em En
| MEDLINE
| ID: mdl-22902861
ABSTRACT
To guide development of new drugs targeting methionyl-tRNA synthetase (MetRS) for treatment of human African trypanosomiasis, crystal structure determinations of Trypanosoma brucei MetRS in complex with its substrate methionine and its intermediate product methionyl-adenylate were followed by those of the enzyme in complex with high-affinity aminoquinolone inhibitors via soaking experiments. Drastic changes in conformation of one of the two enzymes in the asymmetric unit allowed these inhibitors to occupy an enlarged methionine pocket and a new so-called auxiliary pocket. Interestingly, a small low-affinity compound caused the same conformational changes, removed the methionine without occupying the methionine pocket, and occupied the previously not existing auxiliary pocket. Analysis of these structures indicates that the binding of the inhibitors is the result of conformational selection, not induced fit.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Trypanosoma brucei brucei
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Aminoquinolinas
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Metionina tRNA Ligase
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Antimaláricos
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article