A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen |
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Authors: | Steegborn Clemens Litvin Tatiana N Hess Kenneth C Capper Austin B Taussig Ronald Buck Jochen Levin Lonny R Wu Hao |
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Institution: | Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA. |
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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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