Allosteric functional switch of neurokinin A-mediated signaling at the neurokinin NK2 receptor: structural exploration.
Fiche publication
Date publication
octobre 2009
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GALZI Jean-Luc, Pr HIBERT Marcel
Tous les auteurs :
Valant C, Maillet E, Bourguignon JJ, Bucher B, Utard V, Galzi JL, Hibert M
Lien Pubmed
Résumé
The neurokinin NK2 receptor is known to pre-exist in equilibrium between at least three states: resting-inactive, calcium-triggering, and cAMP-producing. Its endogeneous ligand, NKA, mainly induces the calcium response. Using a FRET-based assay, we have previously discovered an allosteric modulator of the NK2 receptor that has the unique ability to discriminate among the two signaling pathways: calcium-signaling is not affected while cAMP signaling is significantly decreased. A series of compounds have been prepared and studied in order to better understand the structural determinants of this allosteric functional switch of a GPCR. Most of them display the same allosteric profile, with smooth pharmacomodulation. One compound however exhibits significantly improved modulatory properties of NKA induced signaling when compared to the original modulator.
Référence
J Med Chem. 2009 Oct 8;52(19):5999-6011.