KcsA potassium channel

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KcsA (Kchannel of streptomyces A) is a prokaryotic potassium channel from the soil bacterium Streptomyces lividans that has been studied extensively in ion channel research. The pH [1] activated protein possesses two transmembrane segments and a highly selective pore region, responsible for the gating and shuttling of K+ ions out of the cell. [2] The amino acid sequence found in the selectivity filter of KcsA is highly conserved among both prokaryotic and eukaryotic K+ voltage channels; [1] [3] as a result, research on KcsA has provided important structural and mechanistic insight on the molecular basis for K+ ion selection and conduction. As one of the most studied ion channels to this day, KcsA is a template for research on K+ channel function and its elucidated structure underlies computational modeling of channel dynamics for both prokaryotic and eukaryotic species. [4]

Contents

KcsA Potassium Channel
1r3j.png
The four subunits forming the channel are drawn in different colors. They surround a central pore, guarded by the selectivity filter made up of the P-loops from each of the subunits. The blue and red dots indicate the boundaries of the lipid bilayer.
Identifiers
SymbolKcsA
Pfam PF07885
InterPro IPR013099
SCOP2 1bl8 / SCOPe / SUPFAM
OPM superfamily 8
OPM protein 1r3j
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

History

KcsA was the first potassium ion channel to be characterized using x-ray crystallography by Roderick MacKinnon and his colleagues in 1998. In the years leading up to this, research on the structure of K+ channels was centered on the use of small toxin binding to reveal the location of the pore and selectivity filter among channel residues. MacKinnon's group theorized the tetrameric arrangement of the transmembrane segments, and even suggested presence of pore-forming “loops” in the filter region made of short segments of amino acids that interacted with K+ ions passing through the channel [5] The discovery of strong sequence homology between KcsA and other channels in the Kv family, including the Shaker protein, attracted the attention of the scientific community especially as the K+ channel signature sequence began to appear in other prokaryotic genes. The simplicity of the two transmembrane helices in KcsA, as opposed to the six in many eukaryotic ion channels, also provided a method to understand the mechanisms of K+ channels conduction at a more rudimentary level, thereby providing even great impetus for the study of KcsA.

The crystal structure of KcsA was solved by the MacKinnon group in 1998 after discovery that removal of the C-terminus cytoplasmic domain of the native protein (residues 126–158) increases the stability of crystallized samples. A model of KcsA at the 3.2A resolution was produced that confirmed the tetrameric arrangement of the protein around a center pore, with one helix of each subunit facing the inside axis and the other facing outwards. [6] Three years later, a higher resolution model was produced by Morais-Cabral and Zhou after monoclonal Fab fragments were attached to KcsA crystals to further stabilize the channel. [7] In the early 2000s, evidence for the occupation of the selectivity filter by two K+ atom during the transport process emerged, based on energy and electrostatic calculations made to model the pore region. Continued investigation of the various opened and closed, inactive and active conformations of KcsA by other imaging methods such as ssNMR and EPR have since provided even more insight into channel structure and the forces gating the switch from channel inactivation to conduction.

In 2007, Riek et al. showed that the channel opening that results from titrating the ion channel from pH 7 to pH 4, corresponds to conformational changes in two regions: transition to the ion-exchanging state of the selectivity filter, and the opening of the arrangement of TM2 at the C-terminus. [8] This model explains the ability of KcsA to simultaneous select for K+ ions while also gating electrical conductance. In 2011, the crystal structure of full length KcsA was resolved to reveal that hindrance by the previously truncated residues permits only straightforward expansion of the intercellular ion passage region of the protein. This research provides a more detailed look into the motion of separate channel regions during ion conduction. [9] In the present day, KcsA studies are focused on using the prokaryotic channel as a model for the channel dynamics of larger eukaryotic K+ channels, including hERG.

Structure

The crystal structure of KcsA. Only two of the four subunits are shown here. The protein is shown in green, backbone carbonyl groups (oxygen = red, carbon = green) and potassium ions (occupying the S2 and S4 sites) and oxygen atoms of water molecules (S1 and S3) are purple and red spheres respectively. 1K4C.png
The crystal structure of KcsA. Only two of the four subunits are shown here. The protein is shown in green, backbone carbonyl groups (oxygen = red, carbon = green) and potassium ions (occupying the S2 and S4 sites) and oxygen atoms of water molecules (S1 and S3) are purple and red spheres respectively.

The structure of KcsA is that of an inverted cone, with a central pore running down the center made up of two transmembrane helices (the outer-helix M1 and the inner-helix M2), which span the lipid bilayer. The channel itself is a tetramer composed of four identical, single-domain subunits (each with two α-helices) arranged so that one M2 helix faces the central pore, while the other M1 helix faces the lipid membrane. The inner helices are tilted by about 25° in relation to the lipid membrane and are slightly kinked, opening up to face the outside of the cell like a flower. [6] These two TM helices are linked by a reentrant loop, dispersed symmetrically around a common axis corresponding to the central pore. The pore region spans approximately 30 amino acid residues and can be divided into three parts: a selectivity filter near the extracellular side, a dilated water-filled cavity at the center, and a closed gate near the cytoplasmic side formed by four packed M2 helices. [6] This architecture is found to be highly conserved in the potassium channel family [10] [11] in both eukaryotes and prokaryotes.

The overall length of the pore is 45 Å, and its diameter varies considerably within the distinct regions of the inner tunnel. Travelling from the intracellular region outwards (bottom to top in the picture) the pore begins with a gate region formed by M2 helices at 18 Å in diameter, and then opens into a wide cavity (~10 Å across) near the middle of the membrane. [6] In these regions, K+ ions are in contact with surrounding water molecules but when they enter the channel from the selectivity filter at the top, the cavity is so narrow that K+ ions must shed any hydrating waters in order to enter the cell. [6] In regards to the amino acid composition of the pore-lining residues within KcsA, the side chains lining the internal pore and cavity are predominantly hydrophobic, but within the selectivity filter polar amino acids are present that contact the dehydrated K+ ions.

Selectivity filter

The wider end of the cone corresponds to the extracellular mouth of the channel made up of pore helices, plus a selectivity filter that is formed by a TVGYG sequence, (Threonine, Valine, Glycine, Tyrosine, Glycine), characteristic of potassium channels. [12] Within this region, coordination between the TVGYG amino acids and incoming K+ ions allows for conduction of ions through the channel. The selectivity filter of KcsA contains four ion binding sites, although it is proposed that only two of these four positions are occupied at one time. The selectivity filter is about 3 Å in diameter. [13] though molecular dynamics simulations suggest the filter is flexible. [14] The presence of TVGYG in the filter region of KcsA is conserved even in more complex eukaryotic channels, thus making KcsA an optimal system for studying K+ channel conductance across species.

Function

KcsA transitions from a closed to open conformation upon protonation of the M2 helix at low pH. Voltage gating results in the collapse of the selectivity filter and subsequent inactivation. Image is adapted from Thompson et al. 2008. Channel Conformation.jpg
KcsA transitions from a closed to open conformation upon protonation of the M2 helix at low pH. Voltage gating results in the collapse of the selectivity filter and subsequent inactivation. Image is adapted from Thompson et al. 2008.

The KcsA channel is considered a model channel because the KcsA structure provides a framework for understanding K+ channel conduction, which has three parts: Potassium selectivity, channel gating by pH sensitivity, and voltage-gated channel inactivation. K+ ion permeation occurs at the upper selectivity filter region of the pore, while pH gating rises from the protonation of transmembrane helices at the end of the pore. At low pH, the M2 helix is protonated, shifting the ion channel from closed to open conformation. [15] As ions flow through the channel, voltage gating mechanisms are thought to induce interactions between Glu71 and Asp80 in the selectivity filter, which destabilize the conductive conformation and facilitate entry into a long-lived nonconducting state that resembles the C-type–inactivation of voltage-dependent channels. [16]

In the nonconducting conformation of KcsA at pH 7, K+ is bound tightly to coordinating oxygens of the selectivity filter and the four TM2 helices converge near the cytoplasmic junction to block the passage of any potassium ions. [8] At pH 4 however, KcsA undergoes millisecond-timescale conformational exchanges filter permeating and nonpermeating states and between the open and closed conformations of the M2 helices. [8] While these distinct conformational changes occur in separate regions of the channel, the molecular behavior of each region is linked by both electrostatic interactions and allostery. [8] The dynamics of this exchange stereochemical configurations in the filter provides the physical basis for simultaneous K+ conductance and gating.

K+selectivity

The sequence TVGYG is especially important for maintaining the potassium specificity of KcsA. The glycines in this selectivity filter sequence have dihedral angles that allow carbonyl oxygen atoms in the protein backbone of the filter to point in one direction, toward the ions along the pore. [5] The glycines and threonine coordinate with the K+ ion, while the side-chains of valine and tyrosine are directed into the protein core to impose geometric constraint on the filter. As a result, the KcsA tetramer harbors four equal spaced K+ binding sites, with each side composed of a cage formed by eight oxygen atoms that sit on the vertices of a cube. The oxygen atoms that surround K+ ions in the filter are arranged like the water molecules that encircle hydrated K+ ions in the cavity of the channel; this suggests that oxygen coordination and binding sites in the selectivity filter are paying for the energetic cost of K+ dehydration. [5] Because the Na+ ion is too small for these K+-sized binding sites, dehydration energy is not compensated and thus, the filter selects against other extraneous ions. [5] Additionally, the KcsA channel is blocked by Cs+ ions and gating requires the presence of Mg2+ ions. [1]

pH Sensitivity

The pH-dependent conductance of KcsA indicates that the opening of the ion channel occurs when the protein is exposed to a more acidic environment. NMR studies performed by the Riek group show that pH sensitivity occurs in both the C-terminal TM2 region of the protein as well as with Tyr78 and Gly79 residues in the selectivity filter. There is evidence to suggest that the main pH sensor is in the cytoplasmic domain. Exchanging negatively charged amino acids for neutral ones made the KcsA channel insensitive to pH even though there were no amino-acid changes at the transmembrane region. [17] [18] In addition, between the pH of 6 and 7, histidine is one of the few titratable side chains of histidines; they are absent in the transmembrane and extracellular segments of TM2 but present at KcsA's C-terminus. This highlights a possible mechanism for the slow opening of KcsA which is particularly pH sensitive, especially as the conformational propagation of channel opening signal from the C-terminus to the selectivity filter could be important in coordinating the structural changes needed for conductance along the entire pore.

NMR studies also suggest that a complex hydrogen bond network between Tyr78, Gly79, Glu71 and Asp80 exists in the KcsA filter region, and further acts as a pH-sensitive trigger for conductance. The mutation of key residues in the region, including E71A, results in a large energy cost of 4 kcal mol−1, equivalent to the loss of the hydrogen bond between Glu71 and Tyr78 and the water-mediated hydrogen bond between Glu71 and Asp80 in KcsA(E71A). These studies further highlight the role of pH gating in KcsA channel function.

Voltage Gating

In 2006, the Perozo group proposed a mechanistic explanation for the effects of voltage fields on KcsA gating. After adding a depolarizing current to the channel, the reorientation of Glu71 towards the intracellular pore occurs, thereby disrupting the Glu71-Asp80 carboxyl-carboxylate pair that initially stabilizes the selectivity filter. The collapse of the filter region prevents entry into or facilitate exit from the inactivated state. [16] Glu71, a key part of the selectivity filter signature sequence that is conserved among K+ ion channels, plays a pivotal role in gating as its ability to reorient itself in the direction of the transmembrane voltage field is able to provide an explanation for voltage gating events in KcsA. The orientation of amino acids in the filter region might play significant physiological role in modulating potassium fluxes in eukaryotes and prokaryotes under steady-state conditions. [16]

Research

Function

The precise mechanism of potassium channel selectivity continues to be studied and debated and multiple models are used to describe different aspects of the selectivity. Models explaining selectivity based on field strength concept developed by George Eisenman [19] based on Coulomb's law have been applied to KcsA. [14] [20] An alternative explanation for the selectivity of KcsA is based on the close-fit model (also known as the snug-fit model) developed by Francisco Bezanilla and Armstrong. [21] The main chain carbonyl oxygen atoms that make up the selectivity filter are held at a precise position that allows them to substitute for water molecules in the hydrated shell of the potassium ion, but they are too far from a sodium ion. Further work has studied thermodynamic differences in ion binding, [22] topological considerations, [23] [24] and the number of continuous ion binding sites. [25]

In addition, a major limitation of crystal structure study and simulations has yet to be discussed: the best resolved and most applied crystal structure of KcsA appears to be that of the ‘closed' form of the channel. This is reasonable as the closed state of the channel is favored at neutral pH, at which the crystal structure was solved by X-ray crystallography. However, the dynamic behavior of KcsA makes analysis of the channel difficult as a crystal structure inevitably provides a static, spatially and temporally averaged image of a channel. To bridge the gap between molecular structure and physiological behavior, an understanding of the atomic resolution dynamics of potassium channels is required.

Applications

Due to the high sequence similarity between the pore of KcsA and other eukaryotic K+ ion channel proteins, KcsA has provided important insight into the behavior of other important voltage conducting proteins such as the drosophilla-derived Shaker and the human hERG potassium channel. KcsA has been used in mutagenesis studies to model the interactions between hERG and various drug compounds. Such tests can screen for drug-hERG channel interactions that cause acquired long QT syndrome, are essential for determining the cardiac safety of new medications. [26] In addition, homology models based on the closed state KcsA crystal structure have been generated computationally to construct a multiple state representation of the hERG cardiac K+ channel. Such models reveal the flexibility of the hERG channel and can consistently predict the binding affinity of a set of diverse ion channel-interacting ligands. Analysis of the complex ligand-hERG structures can be used to guide the synthesis of drug analogs with reduced hERG liability, based on drug structure and docking potential. [27]

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">Potassium channel</span> Ion channel that selectively passes K+

Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cell functions.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span> Family of transport proteins

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

<span class="mw-page-title-main">Dendrotoxin</span> Chemical compound

Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes (Dendroaspis) that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctions. Because of their high potency and selectivity for potassium channels, dendrotoxins have proven to be extremely useful as pharmacological tools for studying the structure and function of these ion channel proteins.

<span class="mw-page-title-main">M2 proton channel</span>

The Matrix-2 (M2) protein is a proton-selective viroporin, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer, where the units are helices stabilized by two disulfide bonds, and is activated by low pH. The M2 protein is encoded on the seventh RNA segment together with the M1 protein. Proton conductance by the M2 protein in influenza A is essential for viral replication.

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

<span class="mw-page-title-main">Kv1.1</span>

Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.

<span class="mw-page-title-main">Voltage-gated potassium channel</span> Class of transport proteins

Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

<span class="mw-page-title-main">Two-pore-domain potassium channel</span> Class of transport proteins

The two-pore-domain or tandem pore domain potassium channels are a family of 15 members that form what is known as leak channels which possess Goldman-Hodgkin-Katz (open) rectification. These channels are regulated by several mechanisms including signaling lipids, oxygen tension, pH, mechanical stretch, and G-proteins. Two-pore-domain potassium channels correspond structurally to a inward-rectifier potassium channel α-subunits. Each inward-rectifier potassium channel α-subunit is composed of two transmembrane α-helices, a pore helix and a potassium ion selectivity filter sequence and assembles into a tetramer forming the complete channel. The two-pore domain potassium channels instead are dimers where each subunit is essentially two α-subunits joined together.

Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct sodium ions, calcium ions and possibly hydrogen ions. Plant TPC1s are non-selective channels. Expression of TPCs are found in both plant vacuoles and animal acidic organelles. These organelles consist of endosomes and lysosomes. TPCs are formed from two transmembrane non-equivalent tandem Shaker-like, pore-forming subunits, dimerized to form quasi-tetramers. Quasi-tetramers appear very similar to tetramers, but are not quite the same. Some key roles of TPCs include calcium dependent responses in muscle contraction(s), hormone secretion, fertilization, and differentiation. Disorders linked to TPCs include membrane trafficking, Parkinson's disease, Ebola, and fatty liver.

<span class="mw-page-title-main">SK channel</span> Protein subfamily of calcium-activated potassium channels

SK channels are a subfamily of calcium-activated potassium channels. They are so called because of their small single channel conductance in the order of 10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory.

<span class="mw-page-title-main">L-type calcium channel</span> Family of transport proteins

The L-type calcium channel is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This channel has four isoforms: Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

<span class="mw-page-title-main">Cation channel superfamily</span> Family of ion channel proteins

The transmembrane cation channel superfamily was defined in InterPro and Pfam as the family of tetrameric ion channels. These include the sodium, potassium, calcium, ryanodine receptor, HCN, CNG, CatSper, and TRP channels. This large group of ion channels apparently includes families 1.A.1, 1.A.2, 1.A.3, and 1.A.4 of the TCDB transporter classification.

<span class="mw-page-title-main">Channel blocker</span> Molecule able to block protein channels, frequently used as pharmaceutical

A channel blocker is the biological mechanism in which a particular molecule is used to prevent the opening of ion channels in order to produce a physiological response in a cell. Channel blocking is conducted by different types of molecules, such as cations, anions, amino acids, and other chemicals. These blockers act as ion channel antagonists, preventing the response that is normally provided by the opening of the channel.

Kaliotoxin (KTX) inhibits potassium flux through the Kv1.3 voltage-gated potassium channel and calcium-activated potassium channels by physically blocking the channel-entrance and inducing a conformational change in the K+-selectivity filter of the channel.

<span class="mw-page-title-main">Gating (electrophysiology)</span>

In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.

References

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  21. ↑ Bezanilla F, Armstrong CM (Nov 1972). "Negative conductance caused by entry of sodium and cesium ions into the potassium channels of squid axons". The Journal of General Physiology. 60 (5): 588–608. doi:10.1085/jgp.60.5.588. PMC   2226091 . PMID   4644327.
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  23. ↑ Thomas M, Jayatilaka D, Corry B (Oct 2007). "The predominant role of coordination number in potassium channel selectivity". Biophysical Journal. 93 (8): 2635–43. Bibcode:2007BpJ....93.2635T. doi:10.1529/biophysj.107.108167. PMC   1989715 . PMID   17573427.
  24. ↑ Bostick DL, Brooks CL (May 2007). "Selectivity in K+ channels is due to topological control of the permeant ion's coordinated state". Proceedings of the National Academy of Sciences of the United States of America. 104 (22): 9260–5. Bibcode:2007PNAS..104.9260B. doi: 10.1073/pnas.0700554104 . PMC   1890482 . PMID   17519335.
  25. ↑ Derebe MG, Sauer DB, Zeng W, Alam A, Shi N, Jiang Y (Jan 2011). "Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites". Proceedings of the National Academy of Sciences of the United States of America. 108 (2): 598–602. Bibcode:2011PNAS..108..598D. doi: 10.1073/pnas.1013636108 . PMC   3021048 . PMID   21187421.
  26. ↑ Sanguinetti MC, Mitcheson JS (Mar 2005). "Predicting drug-hERG channel interactions that cause acquired long QT syndrome". Trends in Pharmacological Sciences. 26 (3): 119–24. doi:10.1016/j.tips.2005.01.003. PMID   15749156.
  27. ↑ Rajamani R, Tounge BA, Li J, Reynolds CH (Mar 2005). "A two-state homology model of the hERG K+ channel: application to ligand binding". Bioorganic & Medicinal Chemistry Letters. 15 (6): 1737–41. doi:10.1016/j.bmcl.2005.01.008. PMID   15745831.
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