9P00

Cryo-EM structure of apo S. Mansoni p97

Summary for 9P00

• Entry DOI: 10.2210/pdb9p00/pdb
• Related: 9OX9
• EMDB information: 71062
• Descriptor: vesicle-fusing ATPase (1 entity in total)
• Functional Keywords: aaa-atpase, endoplasmic reticulum, hexamer, chaperone
• Biological source: Schistosoma mansoni
• Total number of polymer chains: 6
• Total formula weight: 556533.56

Authors

Stephens, D.R.,Han, Y.,Chen, Z.,Collins, J.J.,Fung, H.Y.J. (deposition date: 2025-06-06, release date: 2025-08-13, Last modification date: 2025-09-10)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.72 Å)