4EG3

Trypanosoma brucei methionyl-tRNA synthetase in complex with product methionyl-adenylate

Summary for 4EG3

• Entry DOI: 10.2210/pdb4eg3/pdb
• Related: 4EG1 4EG4 4EG5 4EG6 4EG7 4EG8 4EGA
• Descriptor: Methionyl-tRNA synthetase, putative, GLYCEROL, [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxy-oxolan-2-yl]methoxy-hydroxy-phosphoryl] (2S)-2-azanyl-4-methylsulfanyl-butanoate, ... (4 entities in total)
• Functional Keywords: aminoacyl-trna synthetase, aars, metrs, parasite, ligase, protein-inhibitor complex, rossmann-fold, translation, nucleotide binding, rossmann fold, trna binding atp binding
• Biological source: Trypanosoma brucei brucei
• Total number of polymer chains: 2
• Total formula weight: 124839.28

Authors

Koh, C.Y.,Kim, J.E.,Shibata, S.,Fan, E.,Verlinde, C.L.M.J.,Hol, W.G.J. (deposition date: 2012-03-30, release date: 2012-09-12, Last modification date: 2024-10-30)

Primary citation

Koh, C.Y.,Kim, J.E.,Shibata, S.,Ranade, R.M.,Yu, M.,Liu, J.,Gillespie, J.R.,Buckner, F.S.,Verlinde, C.L.,Fan, E.,Hol, W.G.
Distinct States of Methionyl-tRNA Synthetase Indicate Inhibitor Binding by Conformational Selection.
Structure, 20:1681-1691, 2012

PubMed 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.

PubMed: 22902861
DOI: 10.1016/j.str.2012.07.011

Experimental method

X-RAY DIFFRACTION (2.94 Å)