8UBR

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

8UBR の概要

• エントリーDOI: 10.2210/pdb8ubr/pdb
• EMDBエントリー: 42101
• 分子名称: Cystic fibrosis transmembrane conductance regulator, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (7 entities in total)
• 機能のキーワード: inhibitor, cftr, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 172100.30

構造登録者

Young, P.G.,Fiedorczuk, K.,Chen, J. (登録日: 2023-09-24, 公開日: 2024-02-21, 最終更新日: 2024-03-20)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.7 Å)