Structural Basis for the Inhibitor and Substrate Specificity of the Unique Fph Serine Hydrolases of Staphylococcus aureus

• DOI: 10.1021/acsinfecdis.0c00503
• Publication Date: 2020-08-31T16:17:52Z
• Authors: Matthias Fellner; Christian S. Lentz; Sam A. Jamieson; Jodi L. Brewster; Linhai Chen; Matthew Bogyo; Peter D. Mace
• Keywords: Serine hydrolase; Virulence factor; Subfamily; Hydrolase; Esterase; Docking (animal)

Staphylococcus aureus is a prevalent bacterial pathogen in both community and hospital settings, its treatment made particularly difficult by resilience within biofilms. Within this niche, serine hydrolase enzymes play key role generating maintaining the biofilm matrix. Activity-based profiling has previously identified family of hydrolases, designated fluorophosphonate-binding hydrolases (Fph's), some which contribute to virulence S. vivo. These 10 Fph proteins have limited annotation few, if any, characterized or mammalian homologues. This suggests unique functions even species. Here we report structures one most abundant members, FphF. Our capture FphF alone, covalently bound substrate analogue small molecule inhibitors that occupy hydrophobic substrate-binding pocket. In line with these findings, show promiscuous esterase activity toward lipid substrates. We present docking studies characterize interactions substrates active site environment, can be extended other members. Comparison esterases wider protein suggest forms new subfamily. data enzymes, including factor FphB, are likely more restricted profiles than work demonstrates clear molecular rationale for specificity fluorophosphonate probes target provides structural template design enhanced hydrolases.