Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
van den Heuvel, Joop
Glickman, J Fraser
Levin, Lonny R
MetadataShow full item record
AbstractThe signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (ACs) and one soluble AC (sAC). Despite similarities in their catalytic domains, these ACs differ in regulation. Transmembrane ACs respond to G proteins, whereas 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 an 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 reveals an allosteric mechanism of inhibition; the compound induces rearrangements of substrate binding residues and of Arg(176), a trigger between the 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) pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. These studies provide support for the future development of sAC-modulating drugs.
CitationBithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. 2016, 291 (18):9776-84 J. Biol. Chem.
AffiliationHelmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- Structural analysis of human soluble adenylyl cyclase and crystal structures of its nucleotide complexes-implications for cyclase catalysis and evolution.
- Authors: Kleinboelting S, van den Heuvel J, Steegborn C
- Issue date: 2014 Sep
- Structure, mechanism, and regulation of soluble adenylyl cyclases - similarities and differences to transmembrane adenylyl cyclases.
- Authors: Steegborn C
- Issue date: 2014 Dec
- Crystal structure of human soluble adenylate cyclase reveals a distinct, highly flexible allosteric bicarbonate binding pocket.
- Authors: Saalau-Bethell SM, Berdini V, Cleasby A, Congreve M, Coyle JE, Lock V, Murray CW, O'Brien MA, Rich SJ, Sambrook T, Vinkovic M, Yon JR, Jhoti H
- Issue date: 2014 Apr
- The inhibitors of soluble adenylate cyclase 2-OHE, KH7, and bithionol compromise mitochondrial ATP production by distinct mechanisms.
- Authors: Jakobsen E, Lange SC, Andersen JV, Desler C, Kihl HF, Hohnholt MC, Stridh MH, Rasmussen LJ, Waagepetersen HS, Bak LK
- Issue date: 2018 Sep
- Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate.
- Authors: Kleinboelting S, Diaz A, Moniot S, van den Heuvel J, Weyand M, Levin LR, Buck J, Steegborn C
- Issue date: 2014 Mar 11