6XIG

X-ray crystal structure of MqnE from Pedobacter heparinus

6XIG の概要

• エントリーDOI: 10.2210/pdb6xig/pdb
• 分子名称: Aminodeoxyfutalosine synthase, IRON/SULFUR CLUSTER, D(-)-TARTARIC ACID, ... (4 entities in total)
• 機能のキーワード: iron-sulfur cluster, radical sam, menaquinone biosynthesis, biosynthetic protein
• 由来する生物種: Pedobacter heparinus (strain ATCC 13125 / DSM 2366 / CIP 104194 / JCM 7457 / NBRC 12017 / NCIMB 9290 / NRRL B-14731 / HIM 762-3)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99204.21

構造登録者

Grove, T.L.,Bonanno, J.B.,Almo, S.C. (登録日: 2020-06-19, 公開日: 2020-07-15, 最終更新日: 2024-03-06)

主引用文献

Carl, A.G.,Harris, L.D.,Feng, M.,Nordstrom, L.U.,Gerfen, G.J.,Evans, G.B.,Silakov, A.,Almo, S.C.,Grove, T.L.
Narrow-Spectrum Antibiotic Targeting of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis.
Biochemistry, 59:2562-2575, 2020

PubMed Abstract: Antibiotic resistance continues to spread at an alarming rate, outpacing the introduction of new therapeutics and threatening to globally undermine health care. There is a crucial need for new strategies that selectively target specific pathogens while leaving the majority of the microbiome untouched, thus averting the debilitating and sometimes fatal occurrences of opportunistic infections. To address these challenges, we have adopted a unique strategy that focuses on oxygen-sensitive proteins, an untapped set of therapeutic targets. MqnE is a member of the radical -adenosyl-l-methionine (RS) superfamily, all of which rely on an oxygen-sensitive [4Fe-4S] cluster for catalytic activity. MqnE catalyzes the conversion of didehydrochorismate to aminofutalosine in the essential menaquinone biosynthetic pathway present in a limited set of species, including the gut pathogen (), making it an attractive target for narrow-spectrum antibiotic development. Indeed, we show that MqnE is inhibited by the mechanism-derived 2-fluoro analogue of didehydrochorismate (2F-DHC) due to accumulation of a radical intermediate under turnover conditions. Structures of MqnE in the apo and product-bound states afford insight into its catalytic mechanism, and electron paramagnetic resonance approaches provide direct spectroscopic evidence consistent with the predicted structure of the radical intermediate. In addition, we demonstrate the essentiality of the menaquinone biosynthetic pathway and unambiguously validate 2F-DHC as a selective inhibitor of growth that exclusively targets MqnE. These data provide the foundation for designing effective therapies and demonstrate proof of principle that radical SAM proteins can be effectively leveraged as therapeutic targets.

PubMed: 32627538
DOI: 10.1021/acs.biochem.0c00070

実験手法

X-RAY DIFFRACTION (1.59 Å)