Molecular interactions of endogenous D-myo-inositol phosphates with the intracellular D-myo-inositol 1,4,5-trisphosphate recognition site.
A systematic effort was made to elucidate the mode of recognition at the inositol 1,4,5-trisphosphate-specific receptor. Eleven D-myo-inositol phosphates were synthesized and tested for Ca(2+)-mobilizing and receptor-binding activities, which included Ins(1,3,4,5,6)P5, Ins(1,2,5,6)P4, Ins(1,3,4,5)P4, Ins(1,3,4,6)P4, Ins(1,4,5,6)P4, Ins(3,4,5,6)P4, Ins(1,3,4)P4, Ins(1,4,5)P3, Ins(1,5,6)P3, Ins(1,4)P2, and Ins(4,5)P2. Of these, Ins(1,4,5)P3, Ins(1,3,4,6)P4, Ins(1,3,4,5)P4, Ins(1,4,5,6)P4, and Ins(4,5)P2 were able to elicit Ca2+ release from rat brain microsomes. Binding experiments suggest that the ability of these polyphosphates to effect Ca2+ mobilization arises from interactions with the Ins(1,4,5)P3-specific receptor. Accordingly, a model accounting for the ligand recognition is proposed. The Ins(1,4,5)P3-binding site is presumably composed of two domains. The anchoring domain binds the 4,5-bisphosphate 6-hydroxy motif. Disruption of this structural feature abolishes the agonist activity. The auxiliary domain exerts long-range interactions with the 1-phosphate, thus enhancing the binding affinity. The stereochemical requirement for this electrostatic interaction is, however, less stringent. Evidence suggests that Ca(2+)-mobilizing inositol phosphates are able to effect productive binding by assuming conformations displaying or mimicking these essential structural features.
Lu
P J
PJ
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Rhode Island, Kingston 02881.
Gou
D M
DM
Shieh
W R
WR
Chen
C S
CS
D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007295:Inositol Phosphates; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C085029:adenophostin A; D015544:Inositol 1,4,5-Trisphosphate; D000241:Adenosine; D002118:Calcium