Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond

  1. Márton A Simon
  2. László Csanády  Is a corresponding author
  1. Semmelweis University, Hungary


The phosphorylation-activated anion channel CFTR is gated by an ATP hydrolysis cycle at its two cytosolic nucleotide binding domains, and is essential for epithelial salt-water transport. A large number of CFTR mutations cause cystic fibrosis. Since recent breakthrough in targeted pharmacotherapy, CFTR mutants with impaired gating are candidates for stimulation by potentiator drugs. Thus, understanding the molecular pathology of individual mutations has become important. The relatively common R117H mutation affects an extracellular loop, but nevertheless causes a strong gating defect. Here we identify a hydrogen bond between the side chain of arginine 117 and the backbone carbonyl group of glutamate 1124 in the cryo-electronmicroscopic structure of phosphorylated, ATP-bound CFTR. We address the functional relevance of that interaction for CFTR gating using macroscopic and microscopic inside-out patch-clamp recordings. Employing thermodynamic double-mutant cycles, we systematically track gating-state dependent changes in the strength of the R117-E1124 interaction. We find that the H-bond is formed only in the open state, but neither in the short-lived "flickery" nor in the long-lived 'interburst' closed state. Loss of this H-bond explains the strong gating phenotype of the R117H mutant, including robustly shortened burst durations and strongly reduced intraburst open probability. The findings may help targeted potentiator design.

Data availability

All data generated or analysed during this study are included in the main text figures, tables, and supporting figures.

Article and author information

Author details

  1. Márton A Simon

    Department of Biochemistry, Semmelweis University, Budapest, Hungary
    Competing interests
    No competing interests declared.
  2. László Csanády

    Department of Biochemistry, Semmelweis University, Budapest, Hungary
    For correspondence
    Competing interests
    László Csanády, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6547-5889


European Union (Horizon 2020 Research and Innovation Program,739593)

  • László Csanády

Magyar Tudományos Akadémia (Lendület Award,LP2017-14/2017)

  • László Csanády

Cystic Fibrosis Foundation (Research Grant,CSANAD21G0)

  • László Csanády

Ministry for Innovation and Technology (New National Excellence Program,ÚNKP-20-3-I-SE-34)

  • Márton A Simon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.


Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Semmelweis University (last approved 06-03-2021, expiration 06-03-2026).

Reviewing Editor

  1. Andrés Jara-Oseguera, The University of Texas at Austin, United States

Publication history

  1. Received: October 13, 2021
  2. Preprint posted: October 21, 2021 (view preprint)
  3. Accepted: December 3, 2021
  4. Accepted Manuscript published: December 6, 2021 (version 1)
  5. Version of Record published: December 15, 2021 (version 2)


© 2021, Simon & Csanády

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Márton A Simon
  2. László Csanády
Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond
eLife 10:e74693.

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