2BW7
A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen
Summary for 2BW7
Entry DOI | 10.2210/pdb2bw7/pdb |
Related | 1WC0 1WC1 1WC3 1WC4 1WC5 1WC6 |
Descriptor | ADENYLATE CYCLASE, DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, MAGNESIUM ION, ... (6 entities in total) |
Functional Keywords | lyase, adenylyl cyclase, camp signaling, catechol estrogen, inhibitor complex, oxidoreductase |
Biological source | SPIRULINA PLATENSIS |
Total number of polymer chains | 4 |
Total formula weight | 99613.84 |
Authors | Steegborn, C.,Litvin, T.N.,Hess, K.C.,Capper, A.B.,Taussig, R.,Buck, J.,Levin, L.R.,Wu, H. (deposition date: 2005-07-12, release date: 2005-07-20, Last modification date: 2024-05-08) |
Primary citation | Steegborn, C.,Litvin, T.N.,Hess, K.C.,Capper, A.B.,Taussig, R.,Buck, J.,Levin, L.R.,Wu, H. A Novel Mechanism for Adenylyl Cyclase Inhibition from the Crystal Structure of its Complex with Catechol Estrogen J.Biol.Chem., 280:31754-, 2005 Cited by PubMed 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. PubMed: 16002394DOI: 10.1074/JBC.M507144200 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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