Distinct states of methionyl-tRNA synthetase indicate inhibitor binding by conformational selection.
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.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Cho Yeow
CY
Koh
Jessica E
JE
Kim
Sayaka
S
Shibata
Ranae M
RM
Ranade
Mingyan
M
Yu
Jiyun
J
Liu
J Robert
JR
Gillespie
Frederick S
FS
Buckner
Christophe L M J
CL
Verlinde
Erkang
E
Fan
Wim G J
WG
Hol
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000737:chemistry; D000634:Aminoquinolines / Q000737:chemistry*; D000962:Antimalarials / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008715:Methionine / Q000031:analogs & derivatives / Q000737:chemistry; D008718:Methionine-tRNA Ligase / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D013499:Surface Properties; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
D000634:Aminoquinolines; D000962:Antimalarials; D001562:Benzimidazoles; D021122:Protein Subunits; C011501:methioninyl adenylate; D000249:Adenosine Monophosphate; D008715:Methionine; D008718:Methionine-tRNA Ligase