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Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore

Author

Listed:
  • Xiaolong Gao

    (University of Missouri-Columbia)

  • Han-I Yeh

    (University of Missouri-Columbia
    National Yang Ming Chiao Tung University, College of Medicine
    National Yang Ming Chiao Tung University)

  • Zhengrong Yang

    (University of Alabama School of Medicine)

  • Chen Fan

    (Science for Life Laboratory, KTH Royal Institute of Technology
    Stockholm University)

  • Fan Jiang

    (University of Alabama School of Medicine)

  • Rebecca J. Howard

    (Science for Life Laboratory, KTH Royal Institute of Technology
    Stockholm University)

  • Erik Lindahl

    (Science for Life Laboratory, KTH Royal Institute of Technology
    Stockholm University)

  • John C. Kappes

    (University of Alabama School of Medicine
    Birmingham Veterans Affairs Medical Center, Veterans Health Administration)

  • Tzyh-Chang Hwang

    (University of Missouri-Columbia
    National Yang Ming Chiao Tung University, College of Medicine
    National Yang Ming Chiao Tung University)

Abstract

Loss-of-function mutations of the CFTR gene cause the life-shortening genetic disease cystic fibrosis (CF), whereas overactivity of CFTR may lead to secretory diarrhea and polycystic kidney disease. While effective drugs targeting the CFTR protein have been developed for the treatment of CF, little progress has been made for diseases caused by hyper-activated CFTR. Here, we solve the cryo-EM structure of CFTR in complex with CFTRinh-172 (Inh-172), a CFTR gating inhibitor with promising potency and efficacy. We find that Inh-172 binds inside the pore of CFTR, interacting with amino acid residues from transmembrane segments (TMs) 1, 6, 8, 9, and 12 through mostly hydrophobic interactions and a salt bridge. Substitution of these residues lowers the apparent affinity of Inh-172. The inhibitor-bound structure reveals re-orientations of the extracellular segment of TMs 1, 8, and 12, supporting an allosteric modulation mechanism involving post-binding conformational changes. This allosteric inhibitory mechanism readily explains our observations that pig CFTR, which preserves all the amino acid residues involved in Inh-172 binding, exhibits a much-reduced sensitivity to Inh-172 and that the apparent affinity of Inh-172 is altered by the CF drug ivacaftor (i.e., VX-770) which enhances CFTR’s activity through binding to a site also comprising TM8.

Suggested Citation

  • Xiaolong Gao & Han-I Yeh & Zhengrong Yang & Chen Fan & Fan Jiang & Rebecca J. Howard & Erik Lindahl & John C. Kappes & Tzyh-Chang Hwang, 2024. "Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50641-1
    DOI: 10.1038/s41467-024-50641-1
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    References listed on IDEAS

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    1. Jesper Levring & Daniel S. Terry & Zeliha Kilic & Gabriel Fitzgerald & Scott C. Blanchard & Jue Chen, 2023. "Author Correction: CFTR function, pathology and pharmacology at single-molecule resolution," Nature, Nature, vol. 617(7961), pages 11-11, May.
    2. David C. Gadsby & Paola Vergani & László Csanády, 2006. "The ABC protein turned chloride channel whose failure causes cystic fibrosis," Nature, Nature, vol. 440(7083), pages 477-483, March.
    3. Jesper Levring & Daniel S. Terry & Zeliha Kilic & Gabriel Fitzgerald & Scott C. Blanchard & Jue Chen, 2023. "CFTR function, pathology and pharmacology at single-molecule resolution," Nature, Nature, vol. 616(7957), pages 606-614, April.
    4. Paola Vergani & Steve W. Lockless & Angus C. Nairn & David C. Gadsby, 2005. "CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains," Nature, Nature, vol. 433(7028), pages 876-880, February.
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