8UBR

Complex of the phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with CFTRinh-172 and ATP/Mg

Summary for 8UBR

• Entry DOI: 10.2210/pdb8ubr/pdb
• EMDB information: 42101
• Descriptor: Cystic fibrosis transmembrane conductance regulator, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: inhibitor, cftr, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 172100.30

Authors

Young, P.G.,Fiedorczuk, K.,Chen, J. (deposition date: 2023-09-24, release date: 2024-02-21, Last modification date: 2024-03-20)

Primary citation

Young, P.G.,Levring, J.,Fiedorczuk, K.,Blanchard, S.C.,Chen, J.
Structural basis for CFTR inhibition by CFTR inh -172.
Proc.Natl.Acad.Sci.USA, 121:e2316675121-e2316675121, 2024

PubMed Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. While activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease. Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTR-172 to an overall resolution of 2.7 Å by cryogenic electron microscopy. We observe that CFTR-172 binds inside the pore near transmembrane helix 8, a critical structural element that links adenosine triphosphate hydrolysis with channel gating. Binding of CFTR-172 stabilizes a conformation in which the chloride selectivity filter is collapsed, and the pore is blocked from the extracellular side of the membrane. Single-molecule fluorescence resonance energy transfer experiments indicate that CFTR-172 inhibits channel gating without compromising nucleotide-binding domain dimerization. Together, these data reconcile previous biophysical observations and provide a molecular basis for the activity of this widely used CFTR inhibitor.

PubMed: 38422021
DOI: 10.1073/pnas.2316675121

Experimental method

ELECTRON MICROSCOPY (2.7 Å)