7L0B

Crystal structure of hydroxyacyl glutathione hydrolase (GloB) from Staphylococcus aureus, apoenzyme

Summary for 7L0B

• Entry DOI: 10.2210/pdb7l0b/pdb
• Descriptor: Hydroxyacylglutathione hydrolase, ZINC ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: glob, esterase, hydrolase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 4
• Total formula weight: 95848.48

Authors

Miller, J.J.,Jez, J.M.,Odom John, A.R. (deposition date: 2020-12-11, release date: 2020-12-30, Last modification date: 2024-11-20)

Primary citation

Miller, J.J.,Shah, I.T.,Hatten, J.,Barekatain, Y.,Mueller, E.A.,Moustafa, A.M.,Edwards, R.L.,Dowd, C.S.,Planet, P.J.,Muller, F.L.,Jez, J.M.,Odom John, A.R.
Structure-guided microbial targeting of antistaphylococcal prodrugs.
Elife, 10:-, 2021

PubMed Abstract: Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. These studies will enable structure-guided design of antistaphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.

PubMed: 34279224
DOI: 10.7554/eLife.66657

Experimental method

X-RAY DIFFRACTION (1.65 Å)