2bw7
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A NOVEL MECHANISM FOR ADENYLYL CYCLASE INHIBITION FROM THE CRYSTAL STRUCTURE OF ITS COMPLEX WITH CATECHOL ESTROGEN
OverviewOverview
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.
About this StructureAbout this Structure
2BW7 is a Single protein structure of sequence from Arthrospira platensis with , , and as ligands. Active as Adenylate cyclase, with EC number 4.6.1.1 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen., Steegborn C, Litvin TN, Hess KC, Capper AB, Taussig R, Buck J, Levin LR, Wu H, J Biol Chem. 2005 Sep 9;280(36):31754-9. Epub 2005 Jul 7. PMID:16002394
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