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A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen
Authors:Steegborn Clemens  Litvin Tatiana N  Hess Kenneth C  Capper Austin B  Taussig Ronald  Buck Jochen  Levin Lonny R  Wu Hao
Institution:Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA.
Abstract:Catechol estrogens are steroid metabolites that 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 non-competitive with respect to the substrate ATP, and we solved the crystal structure of a catechol estrogen bound to a soluble adenylyl cyclase from Spirulina 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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