Fellner_2020_ACS.Infect.Dis_6_2771

Reference

Title : Structural basis for the inhibitor and substrate specificity of the unique Fph serine hydrolases of Staphylococcus aureus - Fellner_2020_ACS.Infect.Dis_6_2771
Author(s) : Fellner M , Lentz CS , Jamieson SA , Brewster JL , Chen L , Bogyo M , Mace PD
Ref : ACS Infect Dis , 6 :2771 , 2020
Abstract :

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

PubMedSearch : Fellner_2020_ACS.Infect.Dis_6_2771
PubMedID: 32865965
Gene_locus related to this paper: staau-MW0741 , staau-MW2456 , staau-SA1143 , staau-SA2240 , staau-SA2306 , staau-SA2367 , staau-SA2422 , staau-SAV0457 , staau-SAV1793 , staau-SAV2188

Related information

Inhibitor KT129    KT130    JCP678
Substrate KT129    KT130    JCP678    4-methylumbelliferyl-heptanoate
Gene_locus KT129    KT130    JCP678    4-methylumbelliferyl-heptanoate    staau-MW0741    staau-MW2456    staau-SA1143    staau-SA2240    staau-SA2306    staau-SA2367    staau-SA2422    staau-SAV0457    staau-SAV1793    staau-SAV2188
Structure KT129    KT130    JCP678    4-methylumbelliferyl-heptanoate    staau-MW0741    staau-MW2456    staau-SA1143    staau-SA2240    staau-SA2306    staau-SA2367    staau-SA2422    staau-SAV0457    staau-SAV1793    staau-SAV2188    6VH9    6VHD    6VHE    6WCX
Chemical KT129    KT130    JCP678    4-methylumbelliferyl-heptanoate    staau-MW0741    staau-MW2456    staau-SA1143    staau-SA2240    staau-SA2306    staau-SA2367    staau-SA2422    staau-SAV0457    staau-SAV1793    staau-SAV2188    6VH9    6VHD    6VHE    6WCX    2-phenylpiperidine-1-carboxylic-acid

Citations formats

Fellner M, Lentz CS, Jamieson SA, Brewster JL, Chen L, Bogyo M, Mace PD (2020)
Structural basis for the inhibitor and substrate specificity of the unique Fph serine hydrolases of Staphylococcus aureus
ACS Infect Dis 6 :2771

Fellner M, Lentz CS, Jamieson SA, Brewster JL, Chen L, Bogyo M, Mace PD (2020)
ACS Infect Dis 6 :2771