7FIO

LecA from Pseudomonas aeruginosa in complex with a synthetic monovalent galactosidic inhibitor

7FIO の概要

• エントリーDOI: 10.2210/pdb7fio/pdb
• 分子名称: PA-I galactophilic lectin, CALCIUM ION, N-[2-[4-[(2S)-3-(2-hydroxyethylamino)-3-oxidanylidene-2-(2-phenoxyethanoylamino)propyl]-1,2,3-triazol-1-yl]ethyl]-4-[(2S,3R,4S,5R,6R)-6-(hydroxymethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]sulfanyl-benzamide, ... (5 entities in total)
• 機能のキーワード: lectin, carbohydrates, glycoconjugate, glycomimetics, leca, 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: 54125.95

構造登録者

Kuhaudomlarp, S.,Siebs, E.,da Silva Figueiredo Celestino Gomes, P.,Fortin, C.,Rognan, D.,Rademacher, C.,Imberty, A.,Titz, A. (登録日: 2021-07-31, 公開日: 2022-02-16, 最終更新日: 2023-11-29)

主引用文献

Siebs, E.,Shanina, E.,Kuhaudomlarp, S.,da Silva Figueiredo Celestino Gomes, P.,Fortin, C.,Seeberger, P.H.,Rognan, D.,Rademacher, C.,Imberty, A.,Titz, A.
Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA.
Chembiochem, 23:e202100563-e202100563, 2022

PubMed Abstract: Pseudomonas aeruginosa is an opportunistic ESKAPE pathogen that produces two lectins, LecA and LecB, as part of its large arsenal of virulence factors. Both carbohydrate-binding proteins are central to the initial and later persistent infection processes, i. e. bacterial adhesion and biofilm formation. The biofilm matrix is a major resistance determinant and protects the bacteria against external threats such as the host immune system or antibiotic treatment. Therefore, the development of drugs against the P. aeruginosa biofilm is of particular interest to restore efficacy of antimicrobials. Carbohydrate-based inhibitors for LecA and LecB were previously shown to efficiently reduce biofilm formations. Here, we report a new approach for inhibiting LecA with synthetic molecules bridging the established carbohydrate-binding site and a central cavity located between two LecA protomers of the lectin tetramer. Inspired by in silico design, we synthesized various galactosidic LecA inhibitors with aromatic moieties targeting this central pocket. These compounds reached low micromolar affinities, validated in different biophysical assays. Finally, X-ray diffraction analysis revealed the interactions of this compound class with LecA. This new mode of action paves the way to a novel route towards inhibition of P. aeruginosa biofilms.

PubMed: 34788491
DOI: 10.1002/cbic.202100563

実験手法

X-RAY DIFFRACTION (1.5 Å)