8FTP

FphH, Staphylococcus aureus fluorophosphonate-binding serine hydrolases H, apo form

Summary for 8FTP

• Entry DOI: 10.2210/pdb8ftp/pdb
• Descriptor: Alpha/beta fold hydrolase, CALCIUM ION (3 entities in total)
• Functional Keywords: fphh, staphylococcus aureus, s. aureus, fluorophosphonate-binding, serine hydrolases, lipase, hydrolase
• Biological source: Staphylococcus aureus USA300-CA-263
• Total number of polymer chains: 2
• Total formula weight: 56991.87

Authors

Fellner, M. (deposition date: 2023-01-12, release date: 2023-10-11, Last modification date: 2023-11-22)

Primary citation

Fellner, M.,Walsh, A.,Dela Ahator, S.,Aftab, N.,Sutherland, B.,Tan, E.W.,Bakker, A.T.,Martin, N.I.,van der Stelt, M.,Lentz, C.S.
Biochemical and Cellular Characterization of the Function of Fluorophosphonate-Binding Hydrolase H (FphH) in Staphylococcus aureus Support a Role in Bacterial Stress Response.
Acs Infect Dis., 9:2119-2132, 2023

PubMed Abstract: The development of new treatment options for bacterial infections requires access to new targets for antibiotics and antivirulence strategies. Chemoproteomic approaches are powerful tools for profiling and identifying novel druggable target candidates, but their functions often remain uncharacterized. Previously, we used activity-based protein profiling in the opportunistic pathogen to identify active serine hydrolases termed fluorophosphonate-binding hydrolases (Fph). Here, we provide the first characterization of FphH, a conserved, putative carboxylesterase (referred to as K in ) at the molecular and cellular level. First, phenotypic characterization of H-deficient transposon mutants revealed phenotypes during growth under nutrient deprivation, biofilm formation, and intracellular survival. Biochemical and structural investigations revealed that FphH acts as an esterase and lipase based on a fold well suited to act on a small to long hydrophobic unbranched lipid group within its substrate and can be inhibited by active site-targeting oxadiazoles. Prompted by a previous observation that H expression was upregulated in response to fusidic acid, we found that FphH can deacetylate this ribosome-targeting antibiotic, but the lack of FphH function did not infer major changes in antibiotic susceptibility. In conclusion, our results indicate a functional role of this hydrolase in stress responses, and hypothetical functions connecting FphH with components of the ribosome rescue system that are conserved in the same gene cluster across are discussed. Our atomic characterization of FphH will facilitate the development of specific FphH inhibitors and probes to elucidate its physiological role and validity as a drug target.

PubMed: 37824340
DOI: 10.1021/acsinfecdis.3c00246

Experimental method

X-RAY DIFFRACTION (1.37 Å)