A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen

doi:10.1074/jbc.M507144200

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Papers In Press, published online ahead of print July 7, 2005
J. Biol. Chem, 10.1074/jbc.M507144200
Submitted on June 30, 2005
Accepted on July 7, 2005

A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen

Clemens Steegborn, Tatiana N. Litvin, Kenneth C. Hess, Austin B. Capper, Ronald Taussig, Jochen Buck, Lonny R. Levin, and Hao Wu

Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021

Corresponding Author: haowu{at}med.cornell.edu

Catechol estrogens are steroid metabolites which elicit physiological responses through binding to a variety of cellular targets. We show here that catechol estrogens directly inhibit soluble adenylyl cyclases and the abundant trans-membrane adenylyl cyclases. Catechol estrogen inhibition is noncompetitive with respect to the substrate ATP, and we solved the crystal structure of a catechol estrogen bound to a soluble adenylyl cyclase from S. platensis in complex with a substrate analog. The catechol estrogen is bound to a newly identified conserved hydrophobic patch, near the active center but distinct from the ATP binding cleft. Inhibitor binding leads to a chelating interaction between the catechol estrogen hydroxyl groups and the catalytic magnesium ion, distorting the active site and trapping the enzyme substrate complex in a non-productive conformation. This novel inhibition mechanism likely applies to other adenylyl cyclase inhibitors, and the identified ligand binding site has important implications for the development of specific adenylyl cyclase inhibitors.

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