8GLS

Complex of human cystic fibrosis transmembrane conductance regulator (CFTR) and Z1834339853

Summary for 8GLS

• Entry DOI: 10.2210/pdb8gls/pdb
• EMDB information: 40207
• Descriptor: Cystic fibrosis transmembrane conductance regulator, human cystic fibrosis transmembrane conductance regulator, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: transporter, ion channel, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 174975.94

Authors

Liu, F.,Chen, J. (deposition date: 2023-03-23, release date: 2024-06-26, Last modification date: 2025-01-08)

Primary citation

Liu, F.,Kaplan, A.L.,Levring, J.,Einsiedel, J.,Tiedt, S.,Distler, K.,Omattage, N.S.,Kondratov, I.S.,Moroz, Y.S.,Pietz, H.L.,Irwin, J.J.,Gmeiner, P.,Shoichet, B.K.,Chen, J.
Structure-based discovery of CFTR potentiators and inhibitors.
Cell, 187:3712-3725.e34, 2024

PubMed Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

PubMed: 38810646
DOI: 10.1016/j.cell.2024.04.046

Experimental method

ELECTRON MICROSCOPY (3.8 Å)