7FJH

LecA from Pseudomonas aeruginosa in complex with 4-Phenylbutyryl hydroxamic acid (CAS: 32153-46-1)

7FJH の概要

• エントリーDOI: 10.2210/pdb7fjh/pdb
• 分子名称: PA-I galactophilic lectin, N-oxidanyl-4-phenyl-butanamide, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: calcium-binding lectins, glycomimetics, 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: 51599.29

構造登録者

Shanina, S.,Kuhaudomlarp, S.,Siebs, E.,Fuchsberger, F.,Denis, M.,da Silva Figueiredo Celstino Gomes, P.,Clausen, M.H.,Seeberger, P.H.,Rognan, D.,Titz, A.,Imberty, A.,Rademacher, C. (登録日: 2021-08-04, 公開日: 2022-06-08, 最終更新日: 2023-11-29)

主引用文献

Shanina, E.,Kuhaudomlarp, S.,Siebs, E.,Fuchsberger, F.F.,Denis, M.,da Silva Figueiredo Celestino Gomes, P.,Clausen, M.H.,Seeberger, P.H.,Rognan, D.,Titz, A.,Imberty, A.,Rademacher, C.
Targeting undruggable carbohydrate recognition sites through focused fragment library design.
Commun Chem, 5:64-64, 2022

PubMed Abstract: Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition and thus, emerged as viable therapeutic targets. However, their hydrophilic nature poses major limitations to the conventional development of drug-like inhibitors. To address this shortcoming, four fragment libraries were screened to identify metal-binding pharmacophores (MBPs) as novel scaffolds for inhibition of Ca-dependent carbohydrate-protein interactions. Here, we show the effect of MBPs on the clinically relevant lectins DC-SIGN, Langerin, LecA and LecB. Detailed structural and biochemical investigations revealed the specificity of MBPs for different Ca-dependent lectins. Exploring the structure-activity relationships of several fragments uncovered the functional groups in the MBPs suitable for modification to further improve lectin binding and selectivity. Selected inhibitors bound efficiently to DC-SIGN-expressing cells. Altogether, the discovery of MBPs as a promising class of Ca-dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns.

PubMed: 36697615
DOI: 10.1038/s42004-022-00679-3

実験手法

X-RAY DIFFRACTION (1.79 Å)