TY - JOUR
T1 - Molecular recognition at the myo-inositol 1,4,5-trisphosphate receptor. 3- Position substituted myo-inositol 1,4,5-trisphosphate analogues reveal the binding and Ca2+ release requirements for high affinity interaction with the myo-inositol 1,4,5-trisphosphate receptor
AU - Wilcox, R. A.
AU - Challiss, R. A.J.
AU - Traynor, J. R.
AU - Fauq, A. H.
AU - Ognayanov, V. I.
AU - Kozikowski, A. P.
AU - Nahorski, S. R.
N1 - Copyright:
Copyright 2004 Elsevier B.V., All rights reserved.
PY - 1994
Y1 - 1994
N2 - Several novel D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) analogues equatorially substituted at the 3-position have been synthesized to probe the structure-activity relationship of the Ins(1,4,5)P3-receptor subsite adjacent to the native 3-hydroxy (3-OH) of Ins(1,4,5)P3. This study was prompted, in part, by our observation that myo-inositol 1,3,4,5- tetrakisphosphate (Ins(1,3,4,5)P4), the 3-position phosphorylated product of Ins(1,4,5)P3 was a full agonist at the Ca2+-mobilizing Ins(1,4,5)P3 receptor of SH-SY5Y cells (Wilcox, R. A., Challiss, R. A. J., Liu, C., Potter, B. V. I., and Nahorski, S. R. (1993) Mol. Pharmacol. 44, 810-817). The 3-position Ins(1,4,5)P3 analogues were equatorially substituted with groups spanning the steric range between the 3-OH of Ins(1,4,5)P3 and the 3- phosphate of Ins(1,3,4,5)P4; in order of increasing 3-position steric bulk these were: 3-fluoro-, 3-chloro-, 3-amino-, 3-bromo-, 3-methoxy-, and 3- phosphorothioate-Ins(1,4,5)P3. The analogues were assessed at the specific Ins(1,4,5)P3 binding-site of bovine adrenal cortex and for Ca2+ mobilizing activity in saponin-permeabilized SH-SY5Y human neuroblastoma cells. A correlation was observed between increasing molecular volume of the 3- position substituent and respective decreases in both affinity and Ca2+ mobilizing efficacy. Further analysis of the data also revealed that Ins(1,4,5)P3 analogues with equatorial 3-OH, 3-phosphate, and 3- phosphorothioate substituents interacted more favorably with Ins(1,4,5)P3 recognition sites than would be predicted by purely steric considerations. In contrast, 3-C-trifluoromethyl-Ins(1,4,5)P3 (which is axially substituted, but retains the native 3-OH of Ins(1,4,5)P3) interacted with Ins(1,4,5)P3 recognition sites with virtually the same potency as Ins(1,4,5)P3, indicating that the binding pocket of the Ins(1,4,5)P3-receptor was not sterically restrictive with respect to axially oriented 3-position substituents. We conclude that the Ins(1,4,5)P3 receptor has favorable non- covalent binding interactions with the equatorial 3-position substituents of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 and that these interactions significantly ameliorate the steric constraints of the Ins(1,4,5)P3 receptor binding pocket.
AB - Several novel D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) analogues equatorially substituted at the 3-position have been synthesized to probe the structure-activity relationship of the Ins(1,4,5)P3-receptor subsite adjacent to the native 3-hydroxy (3-OH) of Ins(1,4,5)P3. This study was prompted, in part, by our observation that myo-inositol 1,3,4,5- tetrakisphosphate (Ins(1,3,4,5)P4), the 3-position phosphorylated product of Ins(1,4,5)P3 was a full agonist at the Ca2+-mobilizing Ins(1,4,5)P3 receptor of SH-SY5Y cells (Wilcox, R. A., Challiss, R. A. J., Liu, C., Potter, B. V. I., and Nahorski, S. R. (1993) Mol. Pharmacol. 44, 810-817). The 3-position Ins(1,4,5)P3 analogues were equatorially substituted with groups spanning the steric range between the 3-OH of Ins(1,4,5)P3 and the 3- phosphate of Ins(1,3,4,5)P4; in order of increasing 3-position steric bulk these were: 3-fluoro-, 3-chloro-, 3-amino-, 3-bromo-, 3-methoxy-, and 3- phosphorothioate-Ins(1,4,5)P3. The analogues were assessed at the specific Ins(1,4,5)P3 binding-site of bovine adrenal cortex and for Ca2+ mobilizing activity in saponin-permeabilized SH-SY5Y human neuroblastoma cells. A correlation was observed between increasing molecular volume of the 3- position substituent and respective decreases in both affinity and Ca2+ mobilizing efficacy. Further analysis of the data also revealed that Ins(1,4,5)P3 analogues with equatorial 3-OH, 3-phosphate, and 3- phosphorothioate substituents interacted more favorably with Ins(1,4,5)P3 recognition sites than would be predicted by purely steric considerations. In contrast, 3-C-trifluoromethyl-Ins(1,4,5)P3 (which is axially substituted, but retains the native 3-OH of Ins(1,4,5)P3) interacted with Ins(1,4,5)P3 recognition sites with virtually the same potency as Ins(1,4,5)P3, indicating that the binding pocket of the Ins(1,4,5)P3-receptor was not sterically restrictive with respect to axially oriented 3-position substituents. We conclude that the Ins(1,4,5)P3 receptor has favorable non- covalent binding interactions with the equatorial 3-position substituents of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 and that these interactions significantly ameliorate the steric constraints of the Ins(1,4,5)P3 receptor binding pocket.
UR - http://www.scopus.com/inward/record.url?scp=0028089803&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028089803&partnerID=8YFLogxK
M3 - Article
C2 - 7929418
AN - SCOPUS:0028089803
SN - 0021-9258
VL - 269
SP - 26815
EP - 26821
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -