7QI1

Crystal structure of human 14-3-3 protein beta in complex with CFTR peptide pS753pS768 and PPI stabilizer CY007424

Summary for 7QI1

• Entry DOI: 10.2210/pdb7qi1/pdb
• Descriptor: 14-3-3 protein theta, Cystic fibrosis transmembrane conductance regulator, ARGININE, ... (7 entities in total)
• Functional Keywords: ppi stabilization, cystic fibrosis, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 116439.39

Authors

Stevers, L.M.,Ottmann, C. (deposition date: 2021-12-14, release date: 2022-05-25, Last modification date: 2024-11-13)

Primary citation

Stevers, L.M.,Wolter, M.,Carlile, G.W.,Macdonald, D.,Richard, L.,Gielkens, F.,Hanrahan, J.W.,Thomas, D.Y.,Chakka, S.K.,Peterson, M.L.,Thomas, H.,Brunsveld, L.,Ottmann, C.
Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR.
Nat Commun, 13:3586-3586, 2022

PubMed Abstract: Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics.

PubMed: 35739107
DOI: 10.1038/s41467-022-31206-6

Experimental method

X-RAY DIFFRACTION (1.76 Å)