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Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases

Author

Listed:
  • Iris D. Zelnik

    (Weizmann Institute of Science)

  • Beatriz Mestre

    (Weizmann Institute of Science)

  • Jonathan J. Weinstein

    (Weizmann Institute of Science)

  • Tamir Dingjan

    (Weizmann Institute of Science)

  • Stav Izrailov

    (Weizmann Institute of Science)

  • Shifra Ben-Dor

    (Weizmann Institute of Science)

  • Sarel J. Fleishman

    (Weizmann Institute of Science)

  • Anthony H. Futerman

    (Weizmann Institute of Science)

Abstract

Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.

Suggested Citation

  • Iris D. Zelnik & Beatriz Mestre & Jonathan J. Weinstein & Tamir Dingjan & Stav Izrailov & Shifra Ben-Dor & Sarel J. Fleishman & Anthony H. Futerman, 2023. "Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases," Nature Communications, Nature, vol. 14(1), pages 1-6, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38047-x
    DOI: 10.1038/s41467-023-38047-x
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    1. 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.
    2. Hongwu Qian & Xin Zhao & Renhong Yan & Xia Yao & Shuai Gao & Xue Sun & Ximing Du & Hongyuan Yang & Catherine C. L. Wong & Nieng Yan, 2020. "Structural basis for catalysis and substrate specificity of human ACAT1," Nature, Nature, vol. 581(7808), pages 333-338, May.
    3. Xuewu Sui & Kun Wang & Nina L. Gluchowski & Shane D. Elliott & Maofu Liao & Tobias C. Walther & Robert V. Farese, 2020. "Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme," Nature, Nature, vol. 581(7808), pages 323-328, May.
    4. 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.
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