8CRL

Crystal structure of LplA1 in complex with the inhibitor C3 (Listeria monocytogenes)

8CRL の概要

• エントリーDOI: 10.2210/pdb8crl/pdb
• 関連するPDBエントリー: 8CRI 8CRJ
• 分子名称: lipoate--protein ligase, ~{N}-[3-[2-(6-aminopurin-9-yl)ethanoylamino]propyl]-5-[(3~{R})-1,2-dithiolan-3-yl]pentanamide, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: lipoate, salvage, anti-infectives, drug development, inhibitor, ligase
• 由来する生物種: Listeria monocytogenes
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77464.68

構造登録者

Dienemann, J.-N.,Chen, S.-Y.,Hitzenberger, M.,Sievert, M.L.,Hacker, S.M.,Prigge, S.T.,Zacharias, M.,Groll, M.,Sieber, S.A. (登録日: 2023-03-08, 公開日: 2023-06-07, 最終更新日: 2023-09-20)

主引用文献

Dienemann, J.N.,Chen, S.Y.,Hitzenberger, M.,Sievert, M.L.,Hacker, S.M.,Prigge, S.T.,Zacharias, M.,Groll, M.,Sieber, S.A.
A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites.
Angew.Chem.Int.Ed.Engl., 62:e202304533-e202304533, 2023

PubMed Abstract: The development of novel anti-infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non-essential in human cells. An LA-based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry. Probe labeling served as a proxy of LPL activity, enabling in situ screenings for cell-permeable LPL inhibitors. Profiling a focused compound library revealed two substrate analogs (LAMe and C3) as inhibitors, which were further validated by binding studies and co-crystallography. Importantly, LAMe exhibited low toxicity in human cells and achieved killing of Plasmodium falciparum in erythrocytes with an EC value of 15 μM, making it the most effective LPL inhibitor reported to date.

PubMed: 37249408
DOI: 10.1002/anie.202304533

実験手法

X-RAY DIFFRACTION (2.6 Å)