title: Synthetic partial agonists reveal key steps in IP3 receptor activation.
abstract: Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are ubiquitous intracellular Ca2+ channels. IP(3) binding to the IP(3)-binding core (IBC) near the N terminus initiates conformational changes that lead to opening of a pore. The mechanisms underlying this process are unresolved. We synthesized 2-O-modified IP(3) analogs that are partial agonists of IP(3)R. These are similar to IP(3) in their interactions with the IBC, but they are less effective than IP(3) in rearranging the relationship between the IBC and the N-terminal suppressor domain (SD), and they open the channel at slower rates. IP(3)R with a mutation in the SD occupying a position similar to the 2-O substituent of the partial agonists has a reduced open probability that is similar for full and partial agonists. Bulky or charged substituents from either the ligand or the SD therefore block obligatory coupling of the IBC and the SD. Analysis of DeltaG for ligand binding shows that IP(3) is recognized by the IBC and conformational changes then propagate entirely via the SD to the pore.
authors: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors: Ana M
authors: AM
authors: Rossi
authors: Andrew M
authors: AM
authors: Riley
authors: Stephen C
authors: SC
authors: Tovey
authors: Taufiq
authors: T
authors: Rahman
authors: Olivier
authors: O
authors: Dellis
authors: Emily J A
authors: EJ
authors: Taylor
authors: Valery G
authors: VG
authors: Veresov
authors: Barry V L
authors: BV
authors: Potter
authors: Colin W
authors: CW
authors: Taylor
mesh_terms: D000818:Animals; D001665:Binding Sites; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D015640:Ion Channel Gating / Q000187:drug effects*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands