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Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-type ATPase modulator

Author

Listed:
  • Meseret T. Haile

    (Columbia University Irving Medical Center)

  • Anurag Shukla

    (Drexel University College of Medicine)

  • James Zhen

    (Columbia University Irving Medical Center)

  • Michael W. Mather

    (Drexel University College of Medicine)

  • Suyash Bhatnagar

    (Drexel University College of Medicine)

  • Joanne M. Morrisey

    (Drexel University College of Medicine)

  • Zhening Zhang

    (Columbia University Irving Medical Center)

  • Akhil B. Vaidya

    (Drexel University College of Medicine)

  • Chi-Min Ho

    (Columbia University Irving Medical Center)

Abstract

The Plasmodium falciparum sodium efflux pump PfATP4 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 3.7 Å cryoEM structure of PfATP4 purified from CRISPR-engineered P. falciparum parasites, revealing a previously unknown, apicomplexan-specific binding partner, PfABP, which forms a conserved, likely modulatory interaction with PfATP4. The discovery of PfABP presents an unexplored avenue for designing PfATP4 inhibitors.

Suggested Citation

  • Meseret T. Haile & Anurag Shukla & James Zhen & Michael W. Mather & Suyash Bhatnagar & Joanne M. Morrisey & Zhening Zhang & Akhil B. Vaidya & Chi-Min Ho, 2025. "Endogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-type ATPase modulator," Nature Communications, Nature, vol. 16(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64815-y
    DOI: 10.1038/s41467-025-64815-y
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    1. Maoxing Zhang & Yin Wang & Xi Chen & Feiyun Xu & Ming Ding & Wenxiu Ye & Yuya Kawai & Yosuke Toda & Yuki Hayashi & Takamasa Suzuki & Houqing Zeng & Liang Xiao & Xin Xiao & Jin Xu & Shiwei Guo & Feng Y, 2021. "Plasma membrane H+-ATPase overexpression increases rice yield via simultaneous enhancement of nutrient uptake and photosynthesis," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Chikashi Toyoshima & Masayoshi Nakasako & Hiromi Nomura & Haruo Ogawa, 2000. "Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution," Nature, Nature, vol. 405(6787), pages 647-655, June.
    3. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    4. Phong T. Nguyen & Christine Deisl & Michael Fine & Trevor S. Tippetts & Emiko Uchikawa & Xiao-chen Bai & Beth Levine, 2022. "Structural basis for gating mechanism of the human sodium-potassium pump," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Kiarash Jamali & Lukas Käll & Rui Zhang & Alan Brown & Dari Kimanius & Sjors H. W. Scheres, 2024. "Automated model building and protein identification in cryo-EM maps," Nature, Nature, vol. 628(8007), pages 450-457, April.
    7. Chi-Min Ho & Josh R. Beck & Mason Lai & Yanxiang Cui & Daniel E. Goldberg & Pascal F. Egea & Z. Hong Zhou, 2018. "Malaria parasite translocon structure and mechanism of effector export," Nature, Nature, vol. 561(7721), pages 70-75, September.
    8. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    9. Yingying Guo & Yuanyuan Zhang & Renhong Yan & Bangdong Huang & Fangfei Ye & Liushu Wu & Ximin Chi & Yi shi & Qiang Zhou, 2022. "Cryo-EM structures of recombinant human sodium-potassium pump determined in three different states," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    10. Akhil B. Vaidya & Joanne M. Morrisey & Zhongsheng Zhang & Sudipta Das & Thomas M. Daly & Thomas D. Otto & Natalie J. Spillman & Matthew Wyvratt & Peter Siegl & Jutta Marfurt & Grennady Wirjanata & Bon, 2014. "Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    11. Deivanayagabarathy Vinayagam & Oleg Sitsel & Uwe Schulte & Cristina E. Constantin & Wout Oosterheert & Daniel Prumbaum & Gerd Zolles & Bernd Fakler & Stefan Raunser, 2025. "Molecular mechanism of ultrafast transport by plasma membrane Ca2+-ATPases," Nature, Nature, vol. 646(8083), pages 236-245, October.
    12. Anne-Marie L. Winther & Maike Bublitz & Jesper L. Karlsen & Jesper V. Møller & John B. Hansen & Poul Nissen & Morten J. Buch-Pedersen, 2013. "The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm," Nature, Nature, vol. 495(7440), pages 265-269, March.
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