Activation of IP(3) receptors by synthetic bisphosphate ligands.
Ca(2+) release by d-myo-inositol 1,4,5-trisphosphate receptors (IP(3)Rs) is widely considered to require the vicinal 4,5-bisphosphate motif of IP(3), with P-5 and P-4 engaging the alpha and beta domains of the binding site; using synthesis and mutagenesis we show that the adenine of synthetic glyconucleotides, through an interaction with Arg504, can replace the interaction of either P-1 or P-5 with the alpha-domain producing, respectively, the most potent bisphosphate agonist yet synthesised and the first agonist of IP(3)R without a vicinal bisphosphate motif; this will stimulate new approaches to IP(3)R ligand design.
Sureshan
Kana M
KM
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, UK Bath BA2 7AY.
Riley
Andrew M
AM
Rossi
Ana M
AM
Tovey
Stephen C
SC
Dedos
Skarlatos G
SG
Taylor
Colin W
CW
Potter
Barry V L
BV
D002118:Calcium / Q000737:chemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010710:Phosphates / Q000737:chemistry* / Q000494:pharmacology*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D010710:Phosphates; D002118:Calcium