Article ; Online: A designed inhibitor of a CLC antiporter blocks function through a unique binding mode.
2012 Volume 19, Issue 11, Page(s) 1460–1470
Abstract: The lack of small-molecule inhibitors for anion-selective transporters and channels has impeded our understanding of the complex mechanisms that underlie ion passage. The ubiquitous CLC "Chloride Channel" family represents a unique target for biophysical ...
| Abstract | The lack of small-molecule inhibitors for anion-selective transporters and channels has impeded our understanding of the complex mechanisms that underlie ion passage. The ubiquitous CLC "Chloride Channel" family represents a unique target for biophysical and biochemical studies because its distinctive protein fold supports both passive chloride channels and secondary-active chloride-proton transporters. Here, we describe the synthesis and characterization of a specific small-molecule inhibitor directed against a CLC antiporter (ClC-ec1). This compound, 4,4'-octanamidostilbene-2,2'-disulfonate (OADS), inhibits ClC-ec1 with low micromolar affinity and has no specific effect on a CLC channel (ClC-1). Inhibition of ClC-ec1 occurs by binding to two distinct intracellular sites. The location of these sites and the lipid dependence of inhibition suggest potential mechanisms of action. This compound will empower research to elucidate differences between antiporter and channel mechanisms and to develop treatments for CLC-mediated disorders. |
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| MeSH term(s) | Antiporters/antagonists & inhibitors ; Antiporters/chemistry ; Antiporters/genetics ; Antiporters/metabolism ; Binding Sites ; Chloride Channels/metabolism ; Escherichia coli Proteins/antagonists & inhibitors ; Escherichia coli Proteins/chemistry ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Lipid Bilayers ; Molecular Dynamics Simulation ; Mutation ; Stilbenes/metabolism ; Stilbenes/pharmacology ; Sulfonic Acids/metabolism ; Sulfonic Acids/pharmacology | |||||
| Chemical Substances | 4,4'-octanamidostilbene-2,2'-disulfonic acid ; Antiporters ; CLC-1 channel ; CLC-ec1 protein, E coli ; Chloride Channels ; Escherichia coli Proteins ; Lipid Bilayers ; Stilbenes ; Sulfonic Acids | |||||
| Language | English | |||||
| Publishing date | 2012-11-21 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 917827-2 | |||||
| ISSN | 1879-1301 ; 1074-5521 | |||||
| ISSN (online) | 1879-1301 | |||||
| ISSN | 1074-5521 | |||||
| DOI | 10.1016/j.chembiol.2012.09.017 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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