Molecular Recognition of Adenophostin, a Very Potent Ca2+ Inducer, at the d-myo-Inositol 1,4,5-Trisphosphate Receptor

• Published in: Biochemistry (Easton) 1999-07, Vol.38 (29), p.9234-9241
• Main Authors: Hotoda, Hitoshi, Murayama, Kazuhiro, Miyamoto, Shuichi, Iwata, Yoriko, Takahashi, Masaaki, Kawase, Yumi, Tanzawa, Kazuhiko, Kaneko, Masakatsu
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - metabolism; Animals; Binding Sites; Calcium - metabolism; Calcium Channels - chemistry; Calcium Channels - metabolism; Cerebellum - metabolism; Glucosides - metabolism; Inositol 1,4,5-Trisphosphate - agonists; Inositol 1,4,5-Trisphosphate - chemistry; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-Trisphosphate Receptors; Microsomes - metabolism; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Nucleic Acid Conformation; Penicillium - chemistry; Rats; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi990114r

The recognition mode of adenophostin A at the d-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor was investigated. Comparison of conformations of Ins(1,4,5)P3 and adenophostin A by using the combination of NMR and molecular mechanics (MM) calculations demonstrated that adenophostin A adopted a moderately extended conformation regarding the distance between the 2‘-phosphoryl group and the 3‘ ‘,4‘ ‘-bisphosphate motif, as suggested previously [Wilcox, R. A. et al. (1995) Mol. Pharmacol. 47, 1204−1211]. Based on the nuclear Overhauser effect (NOE) observed between 3‘-H and 1‘ ‘-H and on MM calculations, the molecular shape of adenophostin A proved to be an extended form at least in solution, in contrast to Wilcox's compactly folded, preliminary hairpin model. GlcdR(2,3‘,4‘)P3, an adenophostin analogue without adenine moiety, was found to be less potent than adenophostin A and almost equipotent to Ins(1,4,5)P3. We propose the possibility that (i) the optimal spatial arrangement of the three phosphoryl groups and/or (ii) the interaction of the adenine moiety of adenophostin A with the putative binding site, if it exists in the vicinity of the Ins(1,4,5)P3-binding site, might account for the exceptional potency of adenophostin A.