Figure 7.

Molecular simulation of nucleotide binding sites and consensus PKC phosphorylation sites at the P2X₃ receptor. A, For visual clarity, the backbone structure (in dark and light blue) of the geometry optimized, monomeric, charged, membrane-embedded, unoccupied human P2X₃ glycoprotein receptor is shown. The structure is viewed parallel to the plane of a membrane. A five-disulfide core (thin yellow lines) has been assumed. The extracellular domain forms a twisted loop that is solvent dependent. The intracellularly occurring N- and C-terminal PKC phosphorylation sites (thick yellow) are denoted by PKC1 (amino acids in positions 12-14) and PKC7 (365-367); the extracellular PKC phosphorylation sites are denoted by PKC2-PKC6 (134-136, 178-180, 196-198, 202-204, and 269-271). The extracellularly occurring potential NBDs (red) are denoted by NBD1-NBD4 (62-66, 171-177, 279-286, and 295-302). The potential filter (white) is probably formed by the residues in positions 333-341. The fully functional receptor is a 3n homomeric (n = 1, 2,...) ion channel. B, Model of a putative interaction of UTP (colors: green, carbon; red, oxygen; white, hydrogen; blue, nitrogen; yellow, phosphorus) with the second putative nucleotide binding domain NBD2 of human P2X₃ (Phe-Thr-Ile-Phe-Lys-Asn, 171-177; red), which is in steric neighborhood of the PKC phosphorylation site PKC3 (amino acids Ser-Ile-Arg in positions 178-180; yellow). The first residue (Asn, green) of the N-glycosylation attachment site (Asn-Phe-Thr-Ile, 170-173) is also shown. The uridine ring of UTP is bound into a lipophilic pocket (Phe171, Ile175); the oxygen atoms of the phosphate groups form hydrogen bonds with the hydrogen donating groups of the residues of Lys-176 and Asn-177.