5A3O

Crystal structure of the LecB lectin from Pseudomonas aeruginosa in complex with Methyl 6-(cinnamido)-6-deoxy-alpha-D-mannopyranoside at 1.6 ansgtrom

5A3O の概要

• エントリーDOI: 10.2210/pdb5a3o/pdb
• 分子名称: FUCOSE-BINDING LECTIN PA-IIL, CALCIUM ION, methyl alpha-D-mannopyranoside, ... (6 entities in total)
• 機能のキーワード: glycoinhibitors, sugar binding protein
• 由来する生物種: PSEUDOMONAS AERUGINOSA
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 48766.69

構造登録者

Sommer, R.,Hauck, D.,Varrot, A.,Audfray, A.,Imberty, A.,Titz, A. (登録日: 2015-06-02, 公開日: 2015-07-22, 最終更新日: 2024-01-10)

主引用文献

Sommer, R.,Hauck, D.,Varrot, A.,Wagner, S.,Audfray, A.,Prestel, A.,Moleer, H.M.,Imberty, A.,Titz, A.
Cinnamide Derivatives of D-Mannose as Inhibitors of the Bacterial Virulence Factor Lecb from Pseudomonas Aeruginosa
Chemistryopen, 4:756-, 2015

PubMed Abstract: Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen with high antibiotic resistance. Its lectin LecB was identified as a virulence factor and is relevant in bacterial adhesion and biofilm formation. Inhibition of LecB with carbohydrate-based ligands results in a decrease in toxicity and biofilm formation. We recently discovered two classes of potent drug-like glycomimetic inhibitors, that is, sulfonamides and cinnamides of d-mannose. Here, we describe the chemical synthesis and biochemical evaluation of more than 20 derivatives with increased potency compared to the unsubstituted cinnamide. The structure-activity relationship (SAR) obtained and the extended biophysical characterization allowed the experimental determination of the binding mode of these cinnamides with LecB. The established surface binding mode now allows future rational structure-based drug design. Importantly, all glycomimetics tested showed extended receptor residence times with half-lives in the 5-20 min range, a prerequisite for therapeutic application. Thus, the glycomimetics described here provide an excellent basis for future development of anti-infectives against this multidrug-resistant pathogen.

PubMed: 27308201
DOI: 10.1002/OPEN.201500162

実験手法

X-RAY DIFFRACTION (1.6 Å)