A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen

Clemens Steegborn, Tatiana N. Litvin, Kenneth C. Hess, Austin B. Capper, Ronald Taussig, Jochen Buck, Lonny R. Levin, Hao Wu

Research output: Contribution to journalArticle

60 Citations (Scopus)

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 hydrosyl 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.

Original languageEnglish (US)
Pages (from-to)31754-31759
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number36
DOIs
StatePublished - Sep 9 2005

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Catechol Estrogens
Adenylyl Cyclases
Crystal structure
Substrates
Adenosine Triphosphate
Spirulina
Metabolites
Chelation
Magnesium
Conformations
Catalytic Domain
Steroids
Binding Sites
Ions
Ligands
Membranes
Enzymes

ASJC Scopus subject areas

  • Biochemistry

Cite this

A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen. / Steegborn, Clemens; Litvin, Tatiana N.; Hess, Kenneth C.; Capper, Austin B.; Taussig, Ronald; Buck, Jochen; Levin, Lonny R.; Wu, Hao.

In: Journal of Biological Chemistry, Vol. 280, No. 36, 09.09.2005, p. 31754-31759.

Research output: Contribution to journalArticle

Steegborn, Clemens ; Litvin, Tatiana N. ; Hess, Kenneth C. ; Capper, Austin B. ; Taussig, Ronald ; Buck, Jochen ; Levin, Lonny R. ; Wu, Hao. / A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 36. pp. 31754-31759.
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