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

Title data

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: The Journal of Biological Chemistry. Vol. 280 (2005) Issue 36 . - pp. 31754-31759.
ISSN 1083-351X
DOI: https://doi.org/10.1074/jbc.M507144200

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 11157750
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 14 Apr 2015 10:16
Last Modified: 16 Jun 2023 08:46
URI: https://eref.uni-bayreuth.de/id/eprint/10137