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Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment

Author

Listed:
  • Aaron P. Owji

    (Columbia University)

  • Jingyun Dong

    (Columbia University)

  • Alec Kittredge

    (Columbia University)

  • Jiali Wang

    (Columbia University)

  • Yu Zhang

    (Columbia University)

  • Tingting Yang

    (Columbia University)

Abstract

Best1 and Best2 are two members of the bestrophin family of anion channels critically involved in the prevention of retinal degeneration and maintenance of intraocular pressure, respectively. Here, we solved glutamate- and γ-aminobutyric acid (GABA)-bound Best2 structures, which delineate an intracellular glutamate binding site and an extracellular GABA binding site on Best2, respectively, identified extracellular GABA as a permeable activator of Best2, and elucidated the co-regulation of Best2 by glutamate, GABA and glutamine synthetase in vivo. We further identified multiple small molecules as activators of the bestrophin channels. Extensive analyses were carried out for a potent activator, 4-aminobenzoic acid (PABA): PABA-bound Best1 and Best2 structures are solved and illustrate the same binding site as in GABA-bound Best2; PABA treatment rescues the functional deficiency of patient-derived Best1 mutations. Together, our results demonstrate the mechanism and potential of multiple small molecule candidates as clinically applicable drugs for bestrophin-associated diseases/conditions.

Suggested Citation

  • Aaron P. Owji & Jingyun Dong & Alec Kittredge & Jiali Wang & Yu Zhang & Tingting Yang, 2024. "Neurotransmitter-bound bestrophin channel structures reveal small molecule drug targeting sites for disease treatment," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54938-z
    DOI: 10.1038/s41467-024-54938-z
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    References listed on IDEAS

    as
    1. Yu Zhang & Alec Kittredge & Nancy Ward & Changyi Ji & Shoudeng Chen & Tingting Yang, 2018. "ATP activates bestrophin ion channels through direct interaction," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. Aaron P. Owji & Jiali Wang & Alec Kittredge & Zada Clark & Yu Zhang & Wayne A. Hendrickson & Tingting Yang, 2022. "Structures and gating mechanisms of human bestrophin anion channels," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Veronica Kane Dickson & Leanne Pedi & Stephen B. Long, 2014. "Structure and insights into the function of a Ca2+-activated Cl− channel," Nature, Nature, vol. 516(7530), pages 213-218, December.
    4. Jiali Wang & Aaron P. Owji & Alec Kittredge & Zada Clark & Yu Zhang & Tingting Yang, 2024. "GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Aaron P. Owji & Kuai Yu & Alec Kittredge & Jiali Wang & Yu Zhang & Tingting Yang, 2022. "Bestrophin-2 and glutamine synthetase form a complex for glutamate release," Nature, Nature, vol. 611(7934), pages 180-187, November.
    Full references (including those not matched with items on IDEAS)

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