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A selective class o...
A selective class of inhibitors for the CLC-Ka chloride ion channel
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- Koster, Anna K. (författare)
- Stanford Univ, Dept Chem, Stanford, CA 94305 USA;Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA
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- Wood, Chase A. P. (författare)
- Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA
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- Thomas-Tran, Rhiannon (författare)
- Stanford Univ, Dept Chem, Stanford, CA 94305 USA
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- Chavan, Tanmay S. (författare)
- Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA
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- Almqvist, Jonas (författare)
- Uppsala universitet,Strukturbiologi
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- Choi, Kee-Hyun (författare)
- Korea Inst Sci & Technol, Mat & Life Sci Res Div, Seoul 02792, South Korea
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- Du Bois, J. (författare)
- Stanford Univ, Dept Chem, Stanford, CA 94305 USA
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- Maduke, Merritt (författare)
- Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA
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(creator_code:org_t)
- 2018-04-18
- 2018
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 115:21, s. E4900-E4909
- Relaterad länk:
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https://europepmc.or...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- CLC proteins are a ubiquitously expressed family of chloride-selective ion channels and transporters. A dearth of pharmacological tools for modulating CLC gating and ion conduction limits investigations aimed at understanding CLC structure/function and physiology. Herein, we describe the design, synthesis, and evaluation of a collection of N-arylated benzimidazole derivatives (BIMs), one of which (BIM1) shows unparalleled (>20-fold) selectivity for CLC-Ka over CLC-Kb, the two most closely related human CLC homologs. Computational docking to a CLC-Ka homology model has identified a BIM1 binding site on the extracellular face of the protein near the chloride permeation pathway in a region previously identified as a binding site for other less selective inhibitors. Results from site-directed mutagenesis experiments are consistent with predictions of this docking model. The residue at position 68 is 1 of only similar to 20 extracellular residues that differ between CLC-Ka and CLC-Kb. Mutation of this residue in CLC-Ka and CLC-Kb (N68D and D68N, respectively) reverses the preference of BIM1 for CLC-Ka over CLC-Kb, thus showing the critical role of residue 68 in establishing BIM1 selectivity. Molecular docking studies together with results from structure-activity relationship studies with 19 BIM derivatives give insight into the increased selectivity of BIM1 compared with other inhibitors and identify strategies for further developing this class of compounds.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- chloride channel
- molecular probes
- electrophysiology
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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