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The net electrostatic potential and hydration of ABCG2 affect substrate transport

Author

Listed:
  • Tomoka Gose

    (St. Jude Children’s Research Hospital)

  • Heather M. Aitken

    (The University of Queensland, Australia)

  • Yao Wang

    (St. Jude Children’s Research Hospital)

  • John Lynch

    (St. Jude Children’s Research Hospital)

  • Evadnie Rampersaud

    (St Jude Children’s Research Hospital)

  • Yu Fukuda

    (St. Jude Children’s Research Hospital)

  • Medb Wills

    (St. Jude Children’s Research Hospital)

  • Stefanie A. Baril

    (St. Jude Children’s Research Hospital)

  • Robert C. Ford

    (The University of Manchester)

  • Anang Shelat

    (St. Jude Children’s Research Hospital)

  • Megan L. O’Mara

    (The University of Queensland, Australia)

  • John D. Schuetz

    (St. Jude Children’s Research Hospital)

Abstract

ABCG2 is a medically important ATP-binding cassette transporter with crucial roles in the absorption and distribution of chemically-diverse toxins and drugs, reducing the cellular accumulation of chemotherapeutic drugs to facilitate multidrug resistance in cancer. ABCG2’s capacity to transport both hydrophilic and hydrophobic compounds is not well understood. Here we assess the molecular basis for substrate discrimination by the binding pocket. Substitution of a phylogenetically-conserved polar residue, N436, to alanine in the binding pocket of human ABCG2 permits only hydrophobic substrate transport, revealing the unique role of N436 as a discriminator. Molecular dynamics simulations show that this alanine substitution alters the electrostatic potential of the binding pocket favoring hydration of the transport pore. This change affects the contact with substrates and inhibitors, abrogating hydrophilic compound transport while retaining the transport of hydrophobic compounds. The N436 residue is also required for optimal transport inhibition of ABCG2, as many inhibitors are functionally impaired by this ABCG2 mutation. Overall, these findings have biomedical implications, broadly extending our understanding of substrate and inhibitor interactions.

Suggested Citation

  • Tomoka Gose & Heather M. Aitken & Yao Wang & John Lynch & Evadnie Rampersaud & Yu Fukuda & Medb Wills & Stefanie A. Baril & Robert C. Ford & Anang Shelat & Megan L. O’Mara & John D. Schuetz, 2023. "The net electrostatic potential and hydration of ABCG2 affect substrate transport," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40610-5
    DOI: 10.1038/s41467-023-40610-5
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    References listed on IDEAS

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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. Benjamin J. Orlando & Maofu Liao, 2020. "ABCG2 transports anticancer drugs via a closed-to-open switch," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Narakorn Khunweeraphong & Daniel Szöllősi & Thomas Stockner & Karl Kuchler, 2019. "The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    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.
    5. Ioannis Manolaridis & Scott M. Jackson & Nicholas M. I. Taylor & Julia Kowal & Henning Stahlberg & Kaspar P. Locher, 2018. "Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states," Nature, Nature, vol. 563(7731), pages 426-430, November.
    6. Qin Yu & Dongchun Ni & Julia Kowal & Ioannis Manolaridis & Scott M. Jackson & Henning Stahlberg & Kaspar P. Locher, 2021. "Structures of ABCG2 under turnover conditions reveal a key step in the drug transport mechanism," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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