Voltage sensor conformations in the open and closed states in ROSETTA structural models of K+ channel

Department of Biochemistry , University of Washington Seattle, Seattle, Washington, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2006; 103(19):7292-7. DOI: 10.1073/pnas.0602350103
Source: PubMed


Voltage-gated ion channels control generation and propagation of action potentials in excitable cells. Significant progress has been made in understanding structure and function of the voltage-gated ion channels, highlighted by the high-resolution open-state structure of the voltage-gated potassium channel, K(v)1.2. However, because the structure of the closed state is unknown, the gating mechanism remains controversial. We adapted the rosetta membrane method to model the structures of the K(v)1.2 and KvAP channels using homology, de novo, and domain assembly methods and selected the most plausible models using a limited number of experimental constraints. Our model of K(v)1.2 in the open state is very similar in overall topology to the x-ray structure of this channel. Modeling of KvAP in the open state suggests that orientation of the voltage-sensing domain relative to the pore-forming domain is considerably different from the orientation in the K(v)1.2 open state and that the magnitude of the vertical movement of S4 is significantly greater. Structural modeling of closed state of K(v)1.2 suggests gating movement that can be viewed as a sum of two previously suggested mechanisms: translation (2-4 A) plus rotation ( approximately 180 degrees ) of the S4 segment as proposed in the original "sliding helix" or "helical screw" models coupled with a rolling motion of the S1-S3 segments around S4, similar to recent "transporter" models of gating. We propose a unified mechanism of voltage-dependent gating for K(v)1.2 and KvAP in which this major conformational change moves the gating charge across the electric field in an analogous way for both channels.

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Available from: Vladimir Yarov-Yarovoy, Feb 24, 2015
    • "is catalyzed by exchange of ion pair partners (Catterall, 1986; Guy and Seetharamulu, 1986; Yarov-Yarovoy et al., 2006, 2012). Extensive structure-function studies now provide strong support for all of the elements of this model [reviewed by Catterall (2010)], and a consensus mechanism for voltage sensor function based on the sliding helix model has been presented by several leading investigators (Vargas et al., 2012). "
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    ABSTRACT: Voltage-gated sodium channels initiate action potentials in nerve, muscle, and other electrically excitable cells. Voltage-gated calcium channels are activated by depolarization during action potentials, and calcium influx through them is the key second messenger of electrical signaling, initiating secretion, contraction, neurotransmission, gene transcription, and many other intracellular processes. Drugs that block sodium channels are used in local anesthesia and treatment of epilepsy, bipolar disorder, chronic pain, and cardiac arrhythymia. Drugs that block calcium channels are used in treatment of epilepsy, chronic pain, and cardiovascular disorders, including hypertension, angina pectoris, and cardiac arrhythmia. The principal pore-forming subunits of voltage-gated sodium and calcium channels are structurally related and are likely to have evolved from ancestral voltage-gated sodium channels that are widely expressed in prokaryotes. Determination of the structure of a bacterial ancestor of voltage-gated sodium and calcium channels at high resolution now allows a three-dimensional view of the binding sites for drugs acting on sodium and calcium channels. In this MiniReview, we outline the different classes of sodium and calcium channel drugs, review studies that have identified amino acid residues that are required for their binding and therapeutic actions, and illustrate how the analogs those key amino acid residues may form drug binding sites in three-dimensional models derived from bacterial channels. The American Society for Pharmacology and Experimental Therapeutics.
    No preview · Article · Apr 2015 · Molecular pharmacology
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    • "Although there is no available atomic-resolution structure of a Kv channel in the resting state, the first four arginines (R1-R4) of Kv1.2 are generally thought to stay in a 'down' position in the resting state compared with the open state46,47. A recent long-time all-atom MD simulation also supports the downward movement of arginines5. "
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    ABSTRACT: Voltage-gated potassium (Kv) channels derive their voltage sensitivity from movement of gating charges in voltage-sensor domains (VSDs). The gating charges translocate through a physical pathway in the VSD to open or close the channel. Previous studies showed that the gating charge pathways of Shaker and Kv1.2-2.1 chimeric channels are occluded, forming the structural basis for the focused electric field and gating charge transfer center. Here, we show that the gating charge pathway of the voltage-gated KCNQ2 potassium channel, activity reduction of which causes epilepsy, can accommodate various small molecule ligands. Combining mutagenesis, molecular simulation and electrophysiological recording, a binding model for the probe activator, ztz240, in the gating charge pathway was defined. This information was used to establish a docking-based virtual screening assay targeting the defined ligand-binding pocket. Nine activators with five new chemotypes were identified, and in vivo experiments showed that three ligands binding to the gating charge pathway exhibit significant anti-epilepsy activity. Identification of various novel activators by virtual screening targeting the pocket supports the presence of a ligand-binding site in the gating charge pathway. The capability of the gating charge pathway to accommodate small molecule ligands offers new insights into the gating charge pathway of the therapeutically relevant KCNQ2 channel.Cell Research advance online publication 25 June 2013; doi:10.1038/cr.2013.82.
    Full-text · Article · Jun 2013 · Cell Research
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    • "Starting from the sliding helix (Larsson et al., 1996; Yang et al., 1996) or helical screw model (Guy and Seetharamulu, 1986; Ahern and Horn, 2005), the transporter model (Starace and Bezanilla, 2001, 2004; Chanda et al., 2005), and the paddle model (Jiang et al., 2003; Ruta et al., 2005), the current understanding converges more and more toward a single consensus model for the gating movement of the voltage sensor (Khalili-Araghi et al., 2010; Vargas et al., 2011; Jensen et al., 2012; Yarov-Yarovoy et al., 2012). According to this consensus, the positive gating charges on the S4 are stabilized by pairwise interactions with anionic charges in S1–S3 aligned along the interface to S4 (Papazian et al., 1995; Tiwari-Woodruff et al., 2000; Yarov-Yarovoy et al., 2006). During activation, the positive charges “jump” from one negative charge to the following one leading to the conformational change of the voltage sensor. "
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    ABSTRACT: Voltage-gated ion channels play a central role in the generation of action potentials in the nervous system. They are selective for one type of ion - sodium, calcium, or potassium. Voltage-gated ion channels are composed of a central pore that allows ions to pass through the membrane and four peripheral voltage sensing domains that respond to changes in the membrane potential. Upon depolarization, voltage sensors in voltage-gated potassium channels (Kv) undergo conformational changes driven by positive charges in the S4 segment and aided by pairwise electrostatic interactions with the surrounding voltage sensor. Structure-function relations of Kv channels have been investigated in detail, and the resulting models on the movement of the voltage sensors now converge to a consensus; the S4 segment undergoes a combined movement of rotation, tilt, and vertical displacement in order to bring 3-4e(+) each through the electric field focused in this region. Nevertheless, the mechanism by which the voltage sensor movement leads to pore opening, the electromechanical coupling, is still not fully understood. Thus, recently, electromechanical coupling in different Kv channels has been investigated with a multitude of techniques including electrophysiology, 3D crystal structures, fluorescence spectroscopy, and molecular dynamics simulations. Evidently, the S4-S5 linker, the covalent link between the voltage sensor and pore, plays a crucial role. The linker transfers the energy from the voltage sensor movement to the pore domain via an interaction with the S6 C-termini, which are pulled open during gating. In addition, other contact regions have been proposed. This review aims to provide (i) an in-depth comparison of the molecular mechanisms of electromechanical coupling in different Kv channels; (ii) insight as to how the voltage sensor and pore domain influence one another; and (iii) theoretical predictions on the movement of the cytosolic face of the Kv channels during gating.
    Full-text · Article · Sep 2012 · Frontiers in Pharmacology
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