Faculty Collaboration Database

Natural variation in the binding pocket of a parasitic flatworm TRPM channel resolves the basis for praziquantel sensitivity. Proc Natl Acad Sci U S A 2023 Jan 03;120(1):e2217732120

Date

12/28/2022

Pubmed ID

36574686

Pubmed Central ID

PMC9910428

DOI

10.1073/pnas.2217732120

Scopus ID

2-s2.0-85144783521 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A schistosome target for PZQ was recently identified- a transient receptor potential ion channel in the melastatin subfamily (TRPM_PZQ)-however, little is known about the properties of TRPM_PZQ in other parasitic flatworms. Here, TRPM_PZQ orthologs were scrutinized from all currently available parasitic flatworm genomes. TRPM_PZQ is present in all parasitic flatworms, and the consensus PZQ binding site was well conserved. Functional profiling of trematode, cestode, and a free-living flatworm TRPM_PZQ ortholog revealed differing sensitives (~300-fold) of these TRPM_PZQ channels toward PZQ, which matched the varied sensitivities of these different flatworms to PZQ. Three loci of variation were defined across the parasitic flatworm TRPM_PZQ pocketome with the identity of an acidic residue in the TRP domain acting as a gatekeeper residue impacting PZQ residency within the TRPM_PZQ ligand binding pocket. In trematodes and cyclophyllidean cestodes, which display high sensitivity to PZQ, this TRP domain residue is an aspartic acid which is permissive for potent activation by PZQ. However, the presence of a glutamic acid residue found in other parasitic and free-living flatworm TRPM_PZQ was associated with lower sensitivity to PZQ. The definition of these different binding pocket architectures explains why PZQ shows high therapeutic effectiveness against specific fluke and tapeworm infections and will help the development of better tailored therapies toward other parasitic infections of humans, livestock, and fish.

Author List

Rohr CM, Sprague DJ, Park SK, Malcolm NJ, Marchant JS

Authors

Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Sang Kyu Park PhD Research Scientist I in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Daniel J. Sprague PhD Postdoctoral Fellow in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cestoda
Platyhelminths
Praziquantel
Schistosoma
TRPM Cation Channels
Trematoda