9DRO

FphE, Staphylococcus aureus fluorophosphonate-binding serine hydrolases E, Oxadiazolone-peptide bound

これはPDB形式変換不可エントリーです。

9DRO の概要

• エントリーDOI: 10.2210/pdb9dro/pdb
• 分子名称: Uncharacterized hydrolase SAUSA300_2518, methyl 2-formyl-2-phenylhydrazine-1-carboxylate, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: fphe, staphylococcus aureus, s. aureus, fluorophosphonate-binding, serine hydrolases, lipase, hydrolase, oxadiazolone
• 由来する生物種: Staphylococcus aureus subsp. aureus USA300
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63035.79

構造登録者

Fellner, M. (登録日: 2024-09-25, 公開日: 2025-03-12, 最終更新日: 2025-03-26)

主引用文献

Wang, S.,Woods, E.C.,Jo, J.,Zhu, J.,Hansel-Harris, A.,Holcomb, M.,Llanos, M.,Pedowitz, N.J.,Upadhyay, T.,Bennett, J.,Fellner, M.,Park, K.W.,Zhang, A.,Valdez, T.A.,Forli, S.,Chan, A.I.,Cunningham, C.N.,Bogyo, M.
An mRNA Display Approach for Covalent Targeting of a Staphylococcus aureus Virulence Factor.
J.Am.Chem.Soc., 147:8312-8325, 2025

PubMed Abstract: () is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding hydrolases (Fphs) that play important roles in lipid metabolism and colonization of a host. Because many of these enzymes are only expressed in bacteria, they are valuable targets for diagnostics and therapeutics. Here, we developed and screened highly diverse cyclic peptide libraries using mRNA display with a genetically encoded oxadiazolone (Ox) electrophile that was previously shown to potently and covalently inhibit multiple Fph enzymes. By performing multiple rounds of counter selections with WT and catalytic dead FphB, we were able to tune the selectivity of the resulting selected cyclic peptides containing the Ox residue toward the active site serine. From our mRNA display hits, we developed potent and selective fluorescent probes that label the active site of FphB at single digit nanomolar concentrations in live bacteria. Taken together, this work demonstrates the potential of using direct genetically encoded electrophiles for mRNA display of covalent binding ligands and identifies potent new probes for FphB that have the potential to be used for diagnostic and therapeutic applications.

PubMed: 40013487
DOI: 10.1021/jacs.4c15713

実験手法

X-RAY DIFFRACTION (1.54 Å)