6D3Q

Crystal structure of Escherichia coli enolase complexed with a natural inhibitor SF2312.

6D3Q の概要

• エントリーDOI: 10.2210/pdb6d3q/pdb
• 分子名称: Enolase, [(3S,5S)-1,5-dihydroxy-2-oxopyrrolidin-3-yl]phosphonic acid, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: enolase, complex, natural inhibitor, sf2312, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 281821.25

構造登録者

Erlandsen, H.,Krucinska, J.,Hazeen, A.,Wright, D. (登録日: 2018-04-16, 公開日: 2019-11-27, 最終更新日: 2023-10-04)

主引用文献

Krucinska, J.,Lombardo, M.N.,Erlandsen, H.,Hazeen, A.,Duay, S.S.,Pattis, J.G.,Robinson, V.L.,May, E.R.,Wright, D.L.
Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate.
Sci Rep, 9:17106-17106, 2019

PubMed Abstract: Many years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery.

PubMed: 31745118
DOI: 10.1038/s41598-019-53301-3

実験手法

X-RAY DIFFRACTION (2.24 Å)