These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: 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.
    Author: Wilcox RA, Challiss RA, Traynor JR, Fauq AH, Ognayanov VI, Kozikowski AP, Nahorski SR.
    Journal: J Biol Chem; 1994 Oct 28; 269(43):26815-21. PubMed ID: 7929418.
    Abstract:
    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 Ca(2+)-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.
    [Abstract] [Full Text] [Related] [New Search]