Filter Flexibility in a Mammalian K Channel: Models and Simulations of Kir6.2 Mutants

Capener, Charlotte E.; Proks, Peter; Ashcroft, Frances M.; Sansom, Mark S.P.

doi:10.1016/s0006-3495(03)75040-1

Cited by 58 publications

(55 citation statements)

References 54 publications

(73 reference statements)

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“…It is possible that these relatively small movements alter the conformation of the selectivity filter and effectively gate the access of K ϩ . The idea of a flexible selectivity filter is supported by observations that the filter adopts one conformation in the presence of low extracellular K ϩ and another in the presence of high extracellular K ϩ (38), and also it was recently shown that different distortions of the filter could produce channels with differing conductance (39). The idea that the selectivity filter might move during channel opening has been suggested previously.…”

Section: Discussionmentioning

confidence: 81%

The Selectivity Filter May Act as the Agonist-activated Gate in the G Protein-activated Kir3.1/Kir3.4 K+ Channel

Claydon

Makary

Dibb

et al. 2003

Journal of Biological Chemistry

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The Kir3.1/Kir3.4 channel is activated by G␤␥ subunits released on binding of acetylcholine to the M 2 muscarinic receptor. A mechanism of channel opening, similar to that for the KcsA and Shaker K ؉ channels, has been suggested that involves translocation of pore lining transmembrane helices and the opening of an intracellular gate at the "bundle crossing" region. However, in the present study, we show that an extracellular gate at the selectivity filter is critical for agonist activation of the Kir3.1/Kir3.4 channel. Increasing the flexibility of the selectivity filter, by disrupting a salt bridge that lies directly behind the filter, abolished both selectivity for K ؉ and agonist activation of the channel. Other mutations within the filter that altered selectivity also altered agonist activation. In contrast, mutations within the filter that did not affect selectivity had little if any effect on agonist activation. Interestingly, mutation of bulky side chain phenylalanine residues at the bundle crossing also altered both agonist activation and selectivity. These results demonstrate a significant correlation between agonist activation and selectivity, which is determined by the selectivity filter, and suggests, therefore, that the selectivity filter may act as the agonistactivated gate in the Kir3.1/Kir3.4 channel.

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Section: Discussionmentioning

confidence: 81%

The Selectivity Filter May Act as the Agonist-activated Gate in the G Protein-activated Kir3.1/Kir3.4 K+ Channel

Claydon

Makary

Dibb

et al. 2003

Journal of Biological Chemistry

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“…66,[70][71][72] Here, the carbonyl flipping of Gly626 (in analogy to the glycine at the same position of other channels) was early observed in the simulations of both the closed and the open channel models. In particular, such a conformational change occurred in the A and B chains in hERG C , and in the A and D chains in hERG O .…”

Section: Sfmentioning

confidence: 86%

“…An additional crystallographic (in the KcsA solved at high resolution, PDB entry: 1K4C 4 ) water molecule located ''behind'' the SF as regards to the pore axis, was found to be fundamental to preserve the conformation of the upper moiety of the filter along the production run. [70][71][72] Such a supplementary water molecule, hereafter reported to as W SF (Fig. 3) seems to provide important interactions with the filter and the remainder of the protein.…”

Section: Protein Setupmentioning

confidence: 99%

“…Furthermore, the intrinsic flexibility of the SF region has been proposed as a main fea- ture for determining the ion selectivity in potassium channels. [82][83][84] According to Sansom and coworkers, 70 to evaluate the mobility of the SF, we monitored the conformation of the u-w dihedral angle combination for the involved residues (namely, those ranging from Ser624 to Gly628, for each subunit) as a percentage over the simulation time (see Fig. 2SI).…”

Section: Sfmentioning

confidence: 99%

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Modeling the hERG potassium channel in a phospholipid bilayer: Molecular dynamics and drug docking studies

2007

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The hERG potassium channel has recently been a matter of extensive studies both at experimental and computational levels, because of its possible involvement in the potentially lethal drug-induced long QT syndrome. In this context, in the absence of an experimentally determined 3D structure, to acquire a detailed description of the channel pore and an understanding of atomic determinants for drug binding is of enormous interest at both academic and industrial levels. To contribute to this aim, we first built the open and closed states of the channel by homology modeling techniques, and then submitted both channel models to ns-time-scale MD simulations in explicit membrane. An in-depth analysis of the dynamical behavior of the channel pore with particular attention to the cavity volume was carried out. Finally, using hERG conformations coming from MD simulations, docking experiments were performed to identify a possible binding mode for the most potent hERG channel blocker so far known, the antihistaminic drug astemizole. We show that the combined use of MD and docking is suitable to identify a possible binding mode of drugs in a fairly good agreement with experiments. Moreover, the exploitation of MD snapshots in the docking experiments allowed us to capture some induced-fit effects related to the side chain conformations of Tyr652 and Phe656, which are residues playing a pivotal role in the hERG drug binding.

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“…Eukaryotic ion channels are difficult to express and purify in the quantities needed for structural work. Thus, insight has come mainly from X-ray crystallographic studies on the cytoplasmic pore of mouse Kir3.1 (42), on the truncated bacterial channels KcsA (43) and KirBac1.1 (44), and on the use of these templates to generate homology models for the K ATP channel (13) or various domains (45,46). KcsA provided the archetypal tetrameric K ϩ pore assembled from subunits with three helical elements: the outer M1, pore, and inner M2 helices.…”

mentioning

confidence: 99%

Toward Linking Structure With Function in ATP-Sensitive K+ Channels

et al. 2004

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Advances in understanding the overall structural features of inward rectifiers and ATP-binding cassette (ABC) transporters are providing novel insight into the architecture of ATP-sensitive K ؉ channels (K ATP channels) (K IR 6.0/SUR) 4 . The structure of the K IR pore has been modeled on bacterial K ؉ channels, while the lipid-A exporter, MsbA, provides a template for the MDR-like core of sulfonylurea receptor (SUR)-1. TMD0, an NH 2 -terminal bundle of five ␣-helices found in SURs, binds to and activates K IR 6.0. The adjacent cytoplasmic L0 linker serves a dual function, acting as a tether to link the MDR-like core to the K IR 6.2/TMD0 complex and exerting bidirectional control over channel gating via interactions with the NH 2 -terminus of the K IR . Homology modeling of the SUR1 core offers the possibility of defining the glibenclamide/sulfonylurea binding pocket. Consistent with 30-year-old studies on the pharmacology of hypoglycemic agents, the pocket is bipartite. Elements of the COOHterminal half of the core recognize a hydrophobic group in glibenclamide, adjacent to the sulfonylurea moiety, to provide selectivity for SUR1, while the benzamido group appears to be in proximity to L0 and the K IR NH 2 -terminus. Diabetes 53 (Suppl. 3):S104 -S112, 2004 T he regulation of insulin secretion from pancreatic ␤-cells in the islets of Langerhans is under the orchestration of multiple conductors. While glucose metabolism and changes in cellular energy status ultimately drive insulin output, a variety of inputs converge to modify the rate of secretion and thus maintain blood glucose levels within normal limits. Understanding the molecular basis of these inputs provides multiple routes for therapeutic intervention to both augment and diminish insulin secretion in disorders of glucose homeostasis. The ionic pathway, particularly ATPsensitive K ϩ channels (K ATP channels), has been an effective target, based on the observations by Janbon and colleagues that treatment with a sulfonamide, 2254 RP, produced severe hypoglycemia, as well as subsequent studies by Loubatiè res that the RP compound stimulated insulin release (rev. in 1-3). In pancreatic ␤-cells, K ATP channels are part of the ionic triggering mechanism that increases insulin secretion in response to increased glucose metabolism. The activity of K ATP channels is modulated by changes in the ATP/ADP ratio. In the absence of nucleotides, these channels are spontaneously active, but binding of ATP to the K IR subunits (the half-maximal inhibitory concentration [IC 50 ] for ATP is ϳ10 mol/l) inhibits activity. This inhibition can be antagonized by MgADP acting through the sulfonylurea receptor (SUR). The coupling of membrane potential with cellular metabolism provides a means to adjust the activity of voltagegated Ca 2ϩ channels and, thus, modulate Ca 2ϩ -dependent insulin exocytosis. K ATP channels are known targets for hypoglycemic sulfonylureas like tolbutamide and glibenclamide and for nonsulfonylureas like nateglinide and repaglinide, which increase insulin ...

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Filter Flexibility in a Mammalian K Channel: Models and Simulations of Kir6.2 Mutants

Cited by 58 publications

References 54 publications

The Selectivity Filter May Act as the Agonist-activated Gate in the G Protein-activated Kir3.1/Kir3.4 K+ Channel

The Selectivity Filter May Act as the Agonist-activated Gate in the G Protein-activated Kir3.1/Kir3.4 K+ Channel

Modeling the hERG potassium channel in a phospholipid bilayer: Molecular dynamics and drug docking studies

Toward Linking Structure With Function in ATP-Sensitive K+ Channels

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