2bw7 | pdb_00002bw7
A NOVEL MECHANISM FOR ADENYLYL CYCLASE INHIBITION FROM THE CRYSTAL STRUCTURE OF ITS COMPLEX WITH CATECHOL ESTROGEN
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| 2bw7, resolution 2.3Å | |||||||||||||
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| Sites: | AC1 | ||||||||||||
| Ligands: | MG, CA, APC and ECS | ||||||||||||
| Activity: | Adenylate cyclase, with EC number 4.6.1.1 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
Overview
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 Structure
2BW7 is a Single protein structure of sequence from Arthrospira platensis. Full crystallographic information is available from OCA.
Reference
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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