PREDICTED LIGAND INTERACTIONS FOR 3',5'-CYCLIC NUCLEOTIDE-GATED CHANNEL BINDING-SITES - COMPARISON OF RETINA AND OLFACTORY BINDING-SITE MODELS

Cyclic nucleotide-gated channels (CNGC) open in response to the bindin g of 3',5'-cyclic nucleotides, Members of the CNGC family vary as much as 100-fold in their ability to respond to cAMP and cGMP. Molecular m odels of the nucleotide binding domains of the bovine retina and catfi sh and rat olfactory CNGCs were built from the crystal structure of cA MP bound to catabolite gene activator protein (CAP) with AMMP, a progr am for molecular mechanics and dynamics, The nucleotide conformation c an be predicted from the number of strong and weak interactions betwee n the purine ring and the binding site, The amino acids predicted to b e important for determining the nucleotide affinity and specificity ar e residues 61, 83 (mediated through a water molecule), 119 and 127 (CA P sequence numbers) which interact with the purine ring, These residue s also dictate the conformation of the ligand in the binding pocket, c GMP is preferentially bound in the syn conformation in bovine retina, bovine olfactory and rat olfactory CNGCs due to Thr83, while either co nformation can bind in catfish olfactory CNGC, cAMP is predicted to bi nd either in syn or anti conformation, depending on the interaction wi th residue 119: the anti conformation is preferentially bound in olfac tory CNGCs.