8AYF

Crystal structure of human Sphingosine-1-phosphate lyase 1

8AYF の概要

• エントリーDOI: 10.2210/pdb8ayf/pdb
• 分子名称: Sphingosine-1-phosphate lyase 1, ACETATE ION, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: s1p, lipid, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110298.79

構造登録者

Giardina, G.,Catalano, F.,Pampalone, G.,Cellini, B. (登録日: 2022-09-02, 公開日: 2023-09-13, 最終更新日: 2024-01-03)

主引用文献

Cellini, B.,Pampalone, G.,Camaioni, E.,Pariano, M.,Catalano, F.,Zelante, T.,Dindo, M.,Macchioni, L.,Di Veroli, A.,Galarini, R.,Paoletti, F.,Davidescu, M.,Stincardini, C.,Vascelli, G.,Bellet, M.M.,Saba, J.,Giovagnoli, S.,Giardina, G.,Romani, L.,Costantini, C.
Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study.
Sci Rep, 13:22692-22692, 2023

PubMed Abstract: Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

PubMed: 38123809
DOI: 10.1038/s41598-023-50121-4

実験手法

X-RAY DIFFRACTION (1.84 Å)