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<p>Our understanding of cellular events is hampered by the gap between the resolution at which we can observe events inside cells and our ability to replicate physiological conditions in test tubes. Here, we show in <i>Plasmodium falciparum</i>, a non-model organism of high medical importance, that this gap can be bridged by using an integrated structural biology approach to visualize events inside the cell at molecular resolution. We determined eight high-resolution structures of the native malarial ribosome in actively translating states inside <i>P.</i> <i>falciparum</i>-infected human erythrocytes using in situ cryo-electron tomography. Following perturbation with a <i>Plasmodium</i>-specific translation inhibitor, we then observed a decrease in elongation factor-bound ribosomal states and an apparent upregulation of ribosome biogenesis in inhibitor-treated parasites. Our work elucidates new molecular details of the malarial translation elongation cycle and demonstrates direct multiscale visualization of drug-induced phenotypic changes in the structure and localization of individual molecules within the native cellular context.</p>

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Integrated structural biology of the native malarial translation machinery and its inhibition by an antimalarial drug

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月18日

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  • Leonie Anton,
  • Wenjing Cheng,
  • Meseret T. Haile,
  • Jerzy M. Dziekan,
  • David W. Cobb,
  • Xiyan Zhu,
  • Leyan Han,
  • Emerson Li,
  • Anjali Nair,
  • Carolyn L. Lee,
  • Hanyu Wang,
  • Hangjun Ke,
  • Guoan Zhang,
  • Emma H. Doud,
  • Alan F. Cowman,
  • Chi-Min Ho

摘要

Our understanding of cellular events is hampered by the gap between the resolution at which we can observe events inside cells and our ability to replicate physiological conditions in test tubes. Here, we show in Plasmodium falciparum, a non-model organism of high medical importance, that this gap can be bridged by using an integrated structural biology approach to visualize events inside the cell at molecular resolution. We determined eight high-resolution structures of the native malarial ribosome in actively translating states inside P. falciparum-infected human erythrocytes using in situ cryo-electron tomography. Following perturbation with a Plasmodium-specific translation inhibitor, we then observed a decrease in elongation factor-bound ribosomal states and an apparent upregulation of ribosome biogenesis in inhibitor-treated parasites. Our work elucidates new molecular details of the malarial translation elongation cycle and demonstrates direct multiscale visualization of drug-induced phenotypic changes in the structure and localization of individual molecules within the native cellular context.