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Bithionol potently inhibits human soluble adenylyl cyclase through binding to the allosteric activator site

Title data

Kleinbölting, Silke ; Ramos-Espiritu, Lavoisier ; Buck, Hannes ; Colis, Laureen ; van den Heuvel, Joop ; Glickman, J. Fraser ; Levin, Lonny R. ; Buck, Jochen ; Steegborn, Clemens:
Bithionol potently inhibits human soluble adenylyl cyclase through binding to the allosteric activator site.
In: The Journal of Biological Chemistry. Vol. 291 (9 March 2016) . - pp. 9776-9784.
ISSN 1083-351X
DOI: https://doi.org/10.1074/jbc.M115.708255

Abstract in another language

The signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (tmACs) and one soluble AC (sAC). Despite similarities in their catalytic domains, these ACs differ in regulation. tmACs respond to G-proteins, while sAC is uniquely activated by bicarbonate. Via bicarbonate regulation, sAC acts as a physiological sensor for pH/bicarbonate/CO2, and it has been implicated as a therapeutic target, e.g., for diabetes, glaucoma and a male contraceptive. Here we identify the bisphenols bithionol and hexachlorophene as potent, sAC-specific inhibitors. Inhibition appears mostly non-competitive with the substrate ATP, indicating that they act via an allosteric site. To analyze the interaction details, we solved a crystal structure of a sAC/bithionol complex. The structure reveals that the compounds are selective for sAC because they bind to the sAC-specific, allosteric binding site for the physiological activator bicarbonate. Structural comparison of the bithionol complex with apo sAC and other sAC/ligand complexes, along with mutagenesis experiments, reveal an allosteric mechanism of inhibition; the compound induces rearrangements of substrate binding residues and of Arg176, a trigger between active site and allosteric site. Our results thus provide (1) novel insights into the communication between allosteric regulatory and active sites; (2) a novel mechanism for sAC inhibition; and (3) first pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. These studies provide support for the future development of sAC modulating drugs.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 26961873
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: Yes
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 14 Mar 2016 10:59
Last Modified: 23 Jun 2016 12:54
URI: https://eref.uni-bayreuth.de/id/eprint/31739