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Endogenous structure of antimalarial target Pf ATP4 reveals new class of apicomplexan P-type ATPase modulators
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Endogenous structure of antimalarial target Pf ATP4 reveals new class of apicomplexan P-type ATPase modulators

Meseret T Haile, Anurag Shukla, James Zhen, Michael W Mather, Suyash Bhatnagar, Zhening Zhang, Akhil B Vaidya and Chi-Min Ho
bioRxiv
25 Feb 2025
DOI: https://doi.org/10.1101/2025.02.25.640208
PMID: 40060536
url
https://www.biorxiv.org/content/biorxiv/early/2025/02/25/2025.02.25.640208.full.pdfView
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Abstract

The Plasmodium falciparum sodium efflux pump Pf ATP4 is a leading antimalarial target, but suffers from a lack of high-resolution structural information needed to identify functionally important features in conserved regions and guide rational design of next generation inhibitors. Here, we determine a 3.7Å cryoEM structure of Pf ATP4 purified from CRISPR-engineered P. falciparum parasites, revealing a previously unknown, apicomplexan-specific binding partner, Pf ABP, which forms a conserved, likely modulatory interaction with Pf ATP4. The discovery of Pf ABP presents a new avenue for designing novel Pf ATP4 inhibitors.The Plasmodium falciparum sodium efflux pump Pf ATP4 is a leading antimalarial target, but suffers from a lack of high-resolution structural information needed to identify functionally important features in conserved regions and guide rational design of next generation inhibitors. Here, we determine a 3.7Å cryoEM structure of Pf ATP4 purified from CRISPR-engineered P. falciparum parasites, revealing a previously unknown, apicomplexan-specific binding partner, Pf ABP, which forms a conserved, likely modulatory interaction with Pf ATP4. The discovery of Pf ABP presents a new avenue for designing novel Pf ATP4 inhibitors.

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