title: Structures of KcsA in complex with symmetrical quaternary ammonium compounds reveal a hydrophobic binding site.
abstract: Potassium channels allow for the passive movement of potassium ions across the cell membrane and are instrumental in controlling the membrane potential in all cell types. Quaternary ammonium (QA) compounds block potassium channels and have long been used to study the functional and structural properties of these channels. Here we describe the interaction between three symmetrical hydrophobic QAs and the prokaryotic potassium channel KcsA. The structures demonstrate the presence of a hydrophobic pocket between the inner helices of KcsA and provide insight into the binding site and blocking mechanism of hydrophobic QAs. The structures also reveal a structurally hidden pathway between the central cavity and the outside membrane environment reminiscent of the lateral fenestration observed in sodium channels that can be accessed through small conformational changes in the pore wall. We propose that the hydrophobic binding pocket stabilizes the alkyl chains of long-chain QA molecules and may play a key role in hydrophobic drug binding in general.
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School , 303 East Chicago Avenue, Chicago, Illinois 60611, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenaeus
authors.forename: Dylan
authors.initials: D
authors.lastname: Burdette
authors.forename: Tobias
authors.initials: T
authors.lastname: Wagner
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Focia
authors.forename: Adrian
authors.initials: A
authors.lastname: Gross
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D015640:Ion Channel Gating; D008958:Models, Molecular; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; C504448:KcsA protein, Streptomyces coelicolor; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds
references.citation: Biochemistry. 2002 Jun 18;41(24):7781-94
references.pmid: 12056910
references.citation: Nature. 2002 May 30;417(6888):515-22
references.pmid: 12037559
references.citation: J Gen Physiol. 1965 May;48:859-72
references.pmid: 14324992
references.citation: Science. 2005 Aug 5;309(5736):897-903
references.pmid: 16002581
references.citation: Biophys J. 1981 May;34(2):271-91
references.pmid: 7236852
references.citation: Nature. 2010 Jul 8;466(7303):203-8
references.pmid: 20613835
references.citation: J Gen Physiol. 1997 May;109(5):527-35
references.pmid: 9154902
references.citation: Assay Drug Dev Technol. 2010 Aug;8(4):427-36
references.pmid: 20233091
references.citation: Nature. 2001 Jun 7;411(6838):657-61
references.pmid: 11395760
references.citation: Biophys J. 2003 May;84(5):2929-42
references.pmid: 12719225
references.citation: J Mol Biol. 2007 Feb 23;366(3):806-14
references.pmid: 17196615
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13357-61
references.pmid: 8917595
references.citation: J Mol Biol. 2004 May 7;338(4):839-46
references.pmid: 15099749
references.citation: Neuron. 1993 Mar;10(3):533-41
references.pmid: 8461140
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):1062-9
references.pmid: 17922012
references.citation: Acta Crystallogr D Biol Crystallogr. 1996 Jul 1;52(Pt 4):826-8
references.pmid: 15299647
references.citation: J Gen Physiol. 1967 May;50(5):1287-302
references.pmid: 6033586
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: Biophys J. 2014 Mar 4;106(5):1070-8
references.pmid: 24606931
references.citation: J Gen Physiol. 1971 Oct;58(4):413-37
references.pmid: 5112659
references.citation: Nature. 2011 Jul 10;475(7356):353-8
references.pmid: 21743477
references.citation: J Mol Biol. 2003 Nov 7;333(5):965-75
references.pmid: 14583193
references.citation: J Gen Physiol. 2006 May;127(5):481-94
references.pmid: 16606688
references.citation: Nat Struct Mol Biol. 2006 Apr;13(4):311-8
references.pmid: 16532009
references.citation: Nature. 2002 May 30;417(6888):523-6
references.pmid: 12037560
references.citation: Science. 1991 Feb 22;251(4996):939-42
references.pmid: 2000494
references.citation: Biophys J. 2001 May;80(5):2167-75
references.pmid: 11325719
references.citation: PLoS Biol. 2007 May;5(5):e121
references.pmid: 17472437
references.citation: Biochemistry. 1998 Jun 23;37(25):8825-31
references.pmid: 9636022
references.citation: J Mol Biol. 2007 Jan 19;365(3):649-62
references.pmid: 17070844
references.citation: Nature. 2001 Oct 25;413(6858):809-13
references.pmid: 11677598
references.citation: Science. 2006 Nov 10;314(5801):1004-7
references.pmid: 17095703
references.citation: Nature. 2013 Sep 5;501(7465):121-4
references.pmid: 23892782
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: Nature. 2010 Jul 8;466(7303):272-5
references.pmid: 20613845
references.citation: Science. 1996 Feb 2;271(5249):653-6
references.pmid: 8571129
references.citation: Nature. 2001 Nov 1;414(6859):43-8
references.pmid: 11689936
references.citation: J Gen Physiol. 1969 Nov;54(5):553-75
references.pmid: 5346528
references.citation: Biochemistry. 2003 Apr 29;42(16):4733-43
references.pmid: 12705837
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Nature. 2007 Nov 15;450(7168):376-82
references.pmid: 18004376
references.citation: J Gen Physiol. 1972 Apr;59(4):388-400
references.pmid: 4112955
references.citation: Science. 1998 Apr 3;280(5360):69-77
references.pmid: 9525859
references.citation: Nature. 2012 May 20;486(7401):135-9
references.pmid: 22678296
references.citation: Mol Pharmacol. 2008 Oct;74(4):1033-45
references.pmid: 18653802
references.citation: Nat Struct Mol Biol. 2005 May;12(5):454-9
references.pmid: 15852022