Journal Article

Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism

Fiedorczuk, Karol, Chen, Jue, Young, Paul G.

2025

Overview

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. Hyperactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) is central to the pathogenesis of secretory diarrheas and autosomal dominant polycystic kidney disease (ADPKD). Here, authors use cryo-EM to show that inhibitor (R)-BPO-27 inhibits CFTR via pore blockade

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/45/269/1147 / 631/535/1258/1259 / 631/57/2283 / 631/92/269/1147 / 82/80 / 82/83 / 9/74 / Adenosine Triphosphate - metabolism / Animals / Binding sites / Competition / Conductance / Cryoelectron Microscopy / Cystic fibrosis / Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors / Cystic Fibrosis Transmembrane Conductance Regulator - chemistry / Cystic Fibrosis Transmembrane Conductance Regulator - genetics / Cystic Fibrosis Transmembrane Conductance Regulator - metabolism / Cystic Fibrosis Transmembrane Conductance Regulator - ultrastructure / Diarrhea / Dimerization / End-stage renal disease / Humanities and Social Sciences / Humans / Hydrolysis / Inhibitors / Kidney diseases / Kidneys / Kinases / Models, Molecular / multidisciplinary / Pathogenesis / Pediatrics / Phosphorylation / Polycystic kidney / Protein Binding / Proteins / Science / Science (multidisciplinary)