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DTSTAMP:20250803T223908Z
DESCRIPTION:Dr. Cedric Govaerts\n\nPermanent researcher\, Senior Associate 
 Professor\, Université Libre de Bruxelles\n\nTalk title: ‘’Nanobodies agai
 nst CFTR: from discovering novel conformations to new therapeutics routes’
 ’\n\nFunctional impairment cystic fibrosis transmembrane conductance regul
 ator (CFTR) anion channel by mutation causes Cystic Fibrosis (CF). The mos
 t frequent mutation is the deletion of phenylalanine508 (F508del) in the f
 irst nucleotide-binding domain (NBD1) that affects the thermodynamic stabi
 lity of the domain. We have developed nanobodies targeting NBD1 of human C
 FTR and demonstrate their ability to stabilize both isolated NBD1 and full
 -length protein. Crystal structures of NBD1-nanobody complexes provide ana
 tomic description of the epitopes and reveal the molecular basis for stabi
 lization. These stabilizing nanobodies\, promote maturation and cell-surfa
 ce expression of F508del-CFTR. This effect is highly synergistic with that
  of approved correctors indicating that their modes of correction are diff
 erent. Subsequently\, we have shown that this rescue leads to recovery of 
 CFTR activity in cellular assays but also forskolin-induced swelling of or
 ganoids derived from CF patients. Our nanobodies also revealed that NBD1 c
 an spontaneously adopt an alternative conformation that departs from the c
 anonical NBD fold previously observed for CFTR and related transporters. C
 rystallography studies reveal that this conformation involves atopological
  reorganization of NBD1. Single-molecule fluorescence resonance energy tra
 nsfer microscopy shows that the equilibrium between the conformations is r
 egulated by ATP binding. However\, under destabilizing conditions\, such a
 s the prominent disease-causing mutation F508el\, this conformational flex
 ibility enables unfolding of the β-subdomain. Our data indicate that in wi
 ld-type CFTR this conformational transition of NBD1 regulates channel func
 tion\, but\, in the presence of the F508del mutation\, it allows domain mi
 sfolding and subsequent protein degradation. Our work provides a framework
  to design conformation-specific therapeutics to prevent noxious transitio
 ns.\n\n \n\nThis seminar will be given online via Zoom. Details in attache
 d poster.\n
DTSTART:20220317T153000Z
DTEND:20220317T163000Z
SUMMARY:CFTRc seminar - Dr. Cedric Govaerts
URL:/cftrc/channels/event/cftrc-seminar-dr-cedric-gova
 erts-338152
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