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We have previously demonstrated that Zn2+ inhibits hormone and forskolin stimulation of cAMP synthesis in intact N18TG2 cells, corresponding plasma membranes, and of recombinant adenylyl cyclase isoforms. If, however, the enzyme is pre-activated by hormone or forskolin, Zn2+ inhibition is attenuated [J. Biol. Chem. 277 (2002) 11859]. We have extended our analyses of this inhibition to investigations of soluble adenylyl cyclase, composed of the CI and CII domains of the full-length protein. The properties of Zn2+ inhibition of the soluble enzyme parallel that of the full-length protein, including the fact that inhibition is not competitive with Mg2+. By monitoring intrinsic and extrinsic fluorescence, we demonstrate changes in enzyme conformers in response to the addition of varied effectors. The data suggest a possible mechanism by which Zn2+ inhibits adenylyl cyclase activity. [Copyright &y& Elsevier]