2BW7: A Novel Mechanism for Adenylyl Cyclase Inhibition From the Crystal Structure of ITS Complex With Catechol Estrogen

Citation:
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.
PDB ID: 2BW7Download
MMDB ID: 34475
PDB Deposition Date: 2005/7/12
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 2BW7: dimeric; determined by author and by software (PQS)
Molecular Components in 2BW7
Label Count Molecule
Proteins (2 molecules)
2
Adenylate Cyclase
Molecule annotation
Chemicals (8 molecules)
1
2
2
2
3
2
4
2
* Click molecule labels to explore molecular sequence information.

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