Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism
Abstract Hyperactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) contributes to secretory diarrhea, a major cause of pediatric mortality worldwide, and autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of end-stage renal disease. Selectiv...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62199-7 |
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| author | Paul G. Young Karol Fiedorczuk Jue Chen |
| author_facet | Paul G. Young Karol Fiedorczuk Jue Chen |
| author_sort | Paul G. Young |
| collection | DOAJ |
| description | Abstract Hyperactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) contributes to secretory diarrhea, a major cause of pediatric mortality worldwide, and autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of end-stage renal disease. Selective CFTR inhibition is a potential therapeutic strategy, with (R)-BPO-27 emerging as a promising candidate. Here, we present a cryo-EM structure of CFTR bound to (R)-BPO-27 at an overall resolution of 2.1 Å. Contrary to the previous hypothesis that it inhibits CFTR current by competition with ATP, we demonstrate that (R)-BPO-27 instead directly occludes the chloride-conducting pore while permitting ATP hydrolysis, thus uncoupling the two activities. Furthermore, we find that inhibitor binding requires some degree of NBD separation, as the inhibition rate inversely correlates with the probability NBD dimerization. These findings clarify the compound’s mechanism and provide a molecular basis for optimizing its clinical potential. |
| format | Article |
| id | doaj-art-d8c237cf45f74a51b85aa65c3fc1f334 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d8c237cf45f74a51b85aa65c3fc1f3342025-08-20T03:46:15ZengNature PortfolioNature Communications2041-17232025-08-011611910.1038/s41467-025-62199-7Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanismPaul G. Young0Karol Fiedorczuk1Jue Chen2Laboratory of Membrane Biology and Biophysics, The Rockefeller UniversityLaboratory of Membrane Biology and Biophysics, The Rockefeller UniversityLaboratory of Membrane Biology and Biophysics, The Rockefeller UniversityAbstract Hyperactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) contributes to secretory diarrhea, a major cause of pediatric mortality worldwide, and autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of end-stage renal disease. Selective CFTR inhibition is a potential therapeutic strategy, with (R)-BPO-27 emerging as a promising candidate. Here, we present a cryo-EM structure of CFTR bound to (R)-BPO-27 at an overall resolution of 2.1 Å. Contrary to the previous hypothesis that it inhibits CFTR current by competition with ATP, we demonstrate that (R)-BPO-27 instead directly occludes the chloride-conducting pore while permitting ATP hydrolysis, thus uncoupling the two activities. Furthermore, we find that inhibitor binding requires some degree of NBD separation, as the inhibition rate inversely correlates with the probability NBD dimerization. These findings clarify the compound’s mechanism and provide a molecular basis for optimizing its clinical potential.https://doi.org/10.1038/s41467-025-62199-7 |
| spellingShingle | Paul G. Young Karol Fiedorczuk Jue Chen Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism Nature Communications |
| title | Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism |
| title_full | Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism |
| title_fullStr | Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism |
| title_full_unstemmed | Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism |
| title_short | Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism |
| title_sort | structure of cftr bound to r bpo 27 unveils a pore blockage mechanism |
| url | https://doi.org/10.1038/s41467-025-62199-7 |
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