Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Proteins that form ion-selective pores in the membrane of cells are integral to many rapid signaling processes, including regulating the rhythm of the heartbeat. In potassium channels, the selectivity filter is critical for both endowing an exquisite selectivity for potassium ions, as well as for controlling the flow of ions through the pore. Subtle rearrangements in the complex hydrogen-bond network that link the selectivity filter to the surrounding pore helices differentiate conducting (open) from nonconducting (inactivated) conformations of the channel. Recent studies suggest that beyond the selectivity filter, inactivation involves widespread rearrangements of the channel protein. Here, we use rate equilibrium free energy relationship analysis to probe the structural changes that occur during selectivity filter gating in Kv11.1 channels, at near atomic resolution. We show that the pore helix plays a crucial dynamic role as a bidirectional interface during selectivity filter gating. We also define the molecular bases of the energetic coupling between the pore helix and outer helix of the pore domain that occurs early in the transition from open to inactivated states, as well as the coupling between the pore helix and inner helix late in the transition. Our data demonstrate that the pore helices are more than just static structural elements supporting the integrity of the selectivity filter; instead they play a crucial dynamic role during selectivity filter gating.
Arnold,
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.
2006, Pubmed
Arnold,
The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling.
2006,
Pubmed Auerbach,
How to turn the reaction coordinate into time.
2007,
Pubmed Bordoli,
Protein structure homology modeling using SWISS-MODEL workspace.
2009,
Pubmed Brugada,
Sudden death associated with short-QT syndrome linked to mutations in HERG.
2004,
Pubmed Chen,
Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels.
2002,
Pubmed
,
Xenbase Clarke,
Domain reorientation and rotation of an intracellular assembly regulate conduction in Kir potassium channels.
2010,
Pubmed Cordero-Morales,
A multipoint hydrogen-bond network underlying KcsA C-type inactivation.
2011,
Pubmed
,
Xenbase Cordero-Morales,
Molecular driving forces determining potassium channel slow inactivation.
2007,
Pubmed
,
Xenbase Cordero-Morales,
Molecular determinants of gating at the potassium-channel selectivity filter.
2006,
Pubmed Cuello,
Structural basis for the coupling between activation and inactivation gates in K(+) channels.
2010,
Pubmed Cuello,
Structural mechanism of C-type inactivation in K(+) channels.
2010,
Pubmed Cymes,
Structure of the transition state of gating in the acetylcholine receptor channel pore: a phi-value analysis.
2002,
Pubmed Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed Ferrer,
Molecular coupling in the human ether-a-go-go-related gene-1 (hERG1) K+ channel inactivation pathway.
2011,
Pubmed
,
Xenbase Fersht,
From the first protein structures to our current knowledge of protein folding: delights and scepticisms.
2008,
Pubmed Fersht,
The folding of an enzyme. I. Theory of protein engineering analysis of stability and pathway of protein folding.
1992,
Pubmed Fersht,
Relationship of Leffler (Bronsted) alpha values and protein folding Phi values to position of transition-state structures on reaction coordinates.
2004,
Pubmed Ficker,
Molecular determinants of dofetilide block of HERG K+ channels.
1998,
Pubmed
,
Xenbase Grosman,
Mapping the conformational wave of acetylcholine receptor channel gating.
2000,
Pubmed Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed Heginbotham,
Mutations in the K+ channel signature sequence.
1994,
Pubmed
,
Xenbase Hoshi,
Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.
1991,
Pubmed
,
Xenbase Hoshi,
C-type inactivation of voltage-gated K+ channels: pore constriction or dilation?
2013,
Pubmed Jackson,
Folding of chymotrypsin inhibitor 2. 1. Evidence for a two-state transition.
1991,
Pubmed Jiang,
X-ray structure of a voltage-dependent K+ channel.
2003,
Pubmed Jiang,
Crystal structure and mechanism of a calcium-gated potassium channel.
2002,
Pubmed Ju,
The pore domain outer helix contributes to both activation and inactivation of the HERG K+ channel.
2009,
Pubmed Kiss,
Contribution of the selectivity filter to inactivation in potassium channels.
1999,
Pubmed Kuo,
Crystal structure of the potassium channel KirBac1.1 in the closed state.
2003,
Pubmed Lees-Miller,
Interactions of H562 in the S5 helix with T618 and S621 in the pore helix are important determinants of hERG1 potassium channel structure and function.
2009,
Pubmed Liu,
Dynamic rearrangement of the outer mouth of a K+ channel during gating.
1996,
Pubmed Long,
Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment.
2007,
Pubmed Long,
Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.
2005,
Pubmed Loots,
Molecular coupling of S4 to a K(+) channel's slow inactivation gate.
2000,
Pubmed Perry,
PD-118057 contacts the pore helix of hERG1 channels to attenuate inactivation and enhance K+ conductance.
2009,
Pubmed
,
Xenbase Purohit,
A stepwise mechanism for acetylcholine receptor channel gating.
2007,
Pubmed Raghuraman,
Mechanism of Cd2+ coordination during slow inactivation in potassium channels.
2012,
Pubmed Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed Seebohm,
Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome.
2001,
Pubmed
,
Xenbase Shealy,
Sequence-function analysis of the K+-selective family of ion channels using a comprehensive alignment and the KcsA channel structure.
2003,
Pubmed Smith,
The inward rectification mechanism of the HERG cardiac potassium channel.
1996,
Pubmed Spector,
Fast inactivation causes rectification of the IKr channel.
1996,
Pubmed
,
Xenbase Stansfeld,
Drug block of the hERG potassium channel: insight from modeling.
2007,
Pubmed Starkus,
Ion conduction through C-type inactivated Shaker channels.
1997,
Pubmed
,
Xenbase Stary,
Toward a consensus model of the HERG potassium channel.
2010,
Pubmed Sun,
A novel mutation in the KCNH2 gene associated with short QT syndrome.
2011,
Pubmed Wang,
Mapping the sequence of conformational changes underlying selectivity filter gating in the K(v)11.1 potassium channel.
2011,
Pubmed Wang,
A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase Yang,
How does the W434F mutation block current in Shaker potassium channels?
1997,
Pubmed
,
Xenbase Yellen,
The voltage-gated potassium channels and their relatives.
2002,
Pubmed Yifrach,
Energetics of pore opening in a voltage-gated K(+) channel.
2002,
Pubmed
,
Xenbase Yu,
Two mechanisms of ion selectivity in protein binding sites.
2010,
Pubmed Zhao,
Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S, which has a dominant negative trafficking defect and a severe phenotype.
2009,
Pubmed Zhou,
Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.
2001,
Pubmed Zhou,
Phi-value analysis of a linear, sequential reaction mechanism: theory and application to ion channel gating.
2005,
Pubmed Zou,
A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation.
1998,
Pubmed
,
Xenbase
