9P01

Cryo-EM structure of S. Mansoni p97 bound to ATPgS

9P01 の概要

• エントリーDOI: 10.2210/pdb9p01/pdb
• 関連するPDBエントリー: 9OX9
• EMDBエントリー: 71063
• 分子名称: vesicle-fusing ATPase, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: aaa-atpase, endoplasmic reticulum, hexamer, chaperone
• 由来する生物種: Schistosoma mansoni
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 563104.19

構造登録者

Stephens, D.R.,Han, Y.,Chen, Z.,Collins, J.J.,Fung, H.Y.J. (登録日: 2025-06-06, 公開日: 2025-08-13, 最終更新日: 2025-09-10)

主引用文献

Stephens, D.R.,Fung, H.Y.J.,Han, Y.,Liang, J.,Chen, Z.,Ready, J.,Collins 3rd, J.J.
A genome-scale drug discovery pipeline uncovers therapeutic targets and a unique p97 allosteric binding site in Schistosoma mansoni.
Proc.Natl.Acad.Sci.USA, 122:e2505710122-e2505710122, 2025

PubMed Abstract: Schistosomes are parasitic flatworms that infect more than 200 million people globally. However, there is a shortage of molecular tools that enable the discovery of potential drug targets within schistosomes. Thus, praziquantel has remained the frontline treatment for schistosomiasis despite known liabilities. Here, we have conducted a genome-wide study in using the human druggable genome as a bioinformatic template to identify essential genes within schistosomes bearing similarity to catalogued drug targets. Then, we assessed these candidate targets in silico using a set of unbiased criteria to determine which possess ideal characteristics for a ready-made drug discovery campaign. Following this prioritization, we pursued a parasite p97 ortholog as a bona-fide drug target for the development of therapeutics to treat schistosomiasis. From this effort, we identified a covalent inhibitor series that kills schistosomes through an on-target killing mechanism by disrupting the ubiquitin proteasome system. Fascinatingly, these inhibitors induce a conformational change in the conserved D2 domain P-loop of schistosome p97 upon modification of Cys519. This conformational change reveals an allosteric binding site adjacent to the D2 domain active site reminiscent of the "DFG" flip in protein kinases. This allosteric binding site can potentially be utilized to generate new classes of species-selective p97 inhibitors. Furthermore, these studies provide a resource for the development of alternative therapeutics for schistosomiasis and a workflow to identify potential drug targets in similar systems with few available molecular tools.

PubMed: 40880532
DOI: 10.1073/pnas.2505710122

実験手法

ELECTRON MICROSCOPY (2.2 Å)