CELL BIOLOGY AND METABOLISM
Exchange of Substrate and Inhibitor Specificities between Adenylyl and Guanylyl Cyclases*

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The active sites of guanylyl and adenylyl cyclases are closely related. The crystal structure of adenylyl cyclase and modeling studies suggest that specificity for ATP or GTP is dictated in part by a few amino acid residues, invariant in each family, that interact with the purine ring of the substrate. By exchanging these residues between guanylyl cyclase and adenylyl cyclase, we can completely change the nucleotide specificity of guanylyl cyclase and convert adenylyl cyclase into a nonselective purine nucleotide cyclase. The activities of these mutant enzymes remain fully responsive to their respective stimulators, sodium nitroprusside and Gsα. The specificity of nucleotide inhibitors of guanylyl and adenylyl cyclases that do not act competitively with respect to substrate are similarly altered, indicative of their action at the active sites of these enzymes.

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This work was supported in part by National Institutes of Health Grant DK46371 and Welch Foundation Grant I-1229 (to S. R. S.), the Patrick E. Haggerty Distinguished Chair in Basic Biomedical Science (to D. L. G.), and by National Institutes of Health Grant GM34497, American Cancer Society Grant RPG-77–001-21-BE, Welch Foundation Grant I-1271, and the Raymond and Ellen Willie Distinguished Chair of Molecular Neuropharmacology (to A. G. G.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Recipient of a Postdoctoral Fellowship from the Medical Research Council of Canada.

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Investigator of the Howard Hughes Medical Institute.