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Large-Scale Structural Rearrangement Of A Serine Hydrolase From Francisella Tularensis Facilitates Catalysis, Ekaterina V. Filippova, Leigh A. Watson, Misty L. Kuhn, Brett Geissler, Daniel Becker

Daniel P. Becker

Tularemia is a deadly, febrile disease caused by infection by the gram-negative bacterium, Francisella tularensis. Members of the ubiquitous serine hydrolase protein family are among current targets to treat diverse bacterial infections. Herein we present a structural and functional study of a novel bacterial carboxylesterase (FTT258) from F. tularensis, a homologue of human acyl protein thioesterase (hAPT1). The structure of FTT258 has been determined in multiple forms, and unexpectedly large conformational changes of a peripheral flexible loop occur in the presence of a mechanistic cyclobutanone ligand. The concomitant changes in this hydrophobic loop and the newly exposed hydrophobic substrate binding …