9I94

Cryo-EM structure of Shigella flexneri LptDE bound by a Bicyclic peptide molecule (Compound 3)

9I94 の概要

• エントリーDOI: 10.2210/pdb9i94/pdb
• EMDBエントリー: 52751
• 分子名称: LPS-assembly protein LptD, Compound 3 - Bicyclic Binding Peptide, LPS-assembly lipoprotein LptE, ... (5 entities in total)
• 機能のキーワード: outer membrane protein, lipid transport, membrane protein
• 由来する生物種: Shigella flexneri; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 113286.72

構造登録者

Allyjaun, S.,Newman, H.,Dunbar, E.,Hardwick, S.W.,Chirgadze, D.Y.,van den Berg, B.,Hubbard, J. (登録日: 2025-02-06, 公開日: 2025-10-15, 最終更新日: 2025-11-05)

主引用文献

Allyjaun, S.,Dunbar, E.,Hardwick, S.W.,Newell, S.,Holding, F.,Rowland, C.E.,St Denis, M.A.,Pellegrino, S.,Arruda Bezerra, G.,Bournakas, N.,Chirgadze, D.Y.,Cooper, L.,Paris, G.,Lewis, N.,Brown, P.,Skynner, M.J.,Dawson, M.J.,Beswick, P.,Hubbard, J.,van den Berg, B.,Newman, H.
High-Throughput Identification and Characterization of LptDE-Binding Bicycle Peptides Using Phage Display and Cryo-EM.
J.Med.Chem., 68:21144-21155, 2025

PubMed Abstract: The lipopolysaccharide (LPS) transport (Lpt) system in Gram-negative bacteria maintains the integrity of the asymmetric bacterial outer membrane (OM). LPS biogenesis systems are essential in most Gram-negative bacteria, with LptDE responsible for the delivery of LPS to the outer leaflet of the OM. As an externally accessible, essential protein, LptDE offers a promising target for inhibitor development without the need for cellular penetration. However, there are no direct inhibitors of LptDE, and drug discovery is made challenging since it is a membrane target without a conventional active site. Here, the bicycle phage display platform was used in combination with cryogenic-electron microscopy (cryo-EM) and surface plasmon resonance to identify and map bicyclic peptide binders to LptDE (SfLptDE). Four distinct epitopes with unique bicycle molecule binding motifs were identified across the SfLptD β-barrel. This method represents a streamlined workflow for the identification and prioritization of hit molecules against LptDE.

PubMed: 41048016
DOI: 10.1021/acs.jmedchem.5c00307

実験手法

ELECTRON MICROSCOPY (2.84 Å)