Distinct States of Methionyl-tRNA Synthetase Indicate Inhibitor Binding by Conformational Selection

• Published in: Structure (London) 2012-10, Vol.20 (10), p.1681-1691
• Main Authors: Koh, Cho Yeow, Kim, Jessica E., Shibata, Sayaka, Ranade, Ranae M., Yu, Mingyan, Liu, Jiyun, Gillespie, J. Robert, Buckner, Frederick S., Verlinde, Christophe L.M.J., Fan, Erkang, Hol, Wim G.J.
• Format: Article
• Language: English
• Subjects: Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemistry; Aminoquinolines - chemistry; Antimalarials - chemistry; Benzimidazoles - chemistry; Catalytic Domain; Crystallography, X-Ray; Hydrogen Bonding; Methionine - analogs & derivatives; Methionine - chemistry; Methionine-tRNA Ligase - chemistry; Models, Molecular; Protein Binding; Protein Structure, Quaternary; Protein Structure, Secondary; Protein Subunits - chemistry; Surface Properties; Trypanosoma brucei brucei - enzymology
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2012.07.011

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. [Display omitted] ► Complexes of MetRS from T. brucei with its substrate, intermediate, and inhibitors ► In crystals, substrate-bound MetRS undergoes extensive changes with inhibitor binding ► The inhibitor-bound conformation is surprisingly similar to the ligand-free state ► This indicates inhibitor binding occurs via conformational selection not by induced fit Trypanosoma brucei MetRS is an important anti-parasitic drug target. Koh et al. report eight crystal structures of the enzyme in complex with its substrate, intermediate, potent inhibitors, and a low affinity compound. Structures analysis shows that inhibitor binding follows the conformational selection model.