Journal article
Mutational analysis of an antimalarial drug target, Pf ATP4
Proceedings of the National Academy of Sciences - PNAS, v 122(2), e2501024122
14 Jan 2025
PMID: 39773028
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Among new antimalarials discovered over the past decade are multiple chemical scaffolds that target
P-type ATPase (
ATP4). This essential protein is a Na
pump responsible for the maintenance of Na
homeostasis.
ATP4 belongs to the type two-dimensional (2D) subfamily of P-type ATPases, for which no structures have been determined. To gain better insight into the structure/function relationship of this validated drug target, we generated a homology model of
ATP4 based on sarco/endoplasmic reticulum Ca
ATPase, a P2A-type ATPase, and refined the model using molecular dynamics in its explicit membrane environment. This model predicted several residues in
ATP4 critical for its function, as well as those that impart resistance to various
ATP4 inhibitors. To validate our model, we developed a genetic system involving merodiploid states of
ATP4 in which the endogenous gene was conditionally expressed, and the second allele was mutated to assess its effect on the parasite. Our model predicted residues involved in Na
coordination as well as the phosphorylation cycle of
ATP4. Phenotypic characterization of these mutants involved assessment of parasite growth, localization of mutated
ATP4, response to treatment with known
ATP4 inhibitors, and evaluation of the downstream consequences of Na
influx. Our results were consistent with modeled predictions of the essentiality of the critical residues. Additionally, our approach confirmed the phenotypic consequences of resistance-associated mutations as well as a potential structural basis for the fitness cost associated with some mutations. Taken together, our approach provides a means to explore the structure/function relationship of essential genes in haploid organisms.
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Details
- Title
- Mutational analysis of an antimalarial drug target, Pf ATP4
- Creators
- Swaksha Rachuri - Drexel UniversityBinod Nepal - Drexel UniversityAnurag Shukla - Drexel UniversityAarti Ramanathan - Drexel UniversityJoanne M Morrisey - Drexel UniversityThomas Daly - Drexel UniversityMichael W Mather - Drexel UniversityLawrence W Bergman - Drexel UniversitySandhya Kortagere - Drexel UniversityAkhil B Vaidya - Drexel University
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 122(2), e2501024122
- Publisher
- PNAS
- Number of pages
- 1
- Grant note
- MCB210021P / Anton 2 Award R01 AI132508 / NIAID NIH HHS R01GM116961 / HHS | NIH | National Institute of General Medical Sciences (NIGMS) R01 AI154499 / NIAID NIH HHS R01AI132508 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01AI154499 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:001439855800027
- Scopus ID
- 2-s2.0-85214974028
- Other Identifier
- 991022018707104721
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- Web of Science research areas
- Biochemistry & Molecular Biology