Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics

Figures

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  FIGURE 1. Prolonged QT interval on ECG caused by hERG channel dysfunction. KCNH2 gene mutations and drugs targeting hERG channel can partially or completely reduce IKr, which mainly function in the third phase of cardiac action potentials, resulting in prolonged action potential duration (APD), shown on the ECG as a prolonged QT interval.

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  FIGURE 2. Single alpha subunit of the previous hERG structure (A), new hERGT structure (B), 3D side view of full hERGT (C), obtained from PDB: 5VA2; hERGT) and single subunit of the hERGT on the cell membrane (D). The classic VGK channel structure contains six transmembrane segments S1-S6, S1-S4 contains charges to form the voltage-sensing domain (VSD), and S5-S6 forms the pore domain (PD) (A). Cryo-electron microscope (cryo-EM) structure hERGT with deletion of the N-terminal 141–350 and the C-terminal 871–1,005 of the non-structural sequence to prevent aggregation during purification (B). Full-length hERGT channel contains four subunits arranged in a circular pattern around a central PD (C-left) and magnifying single subunit, colored to distinguish different domains (C-right). The color-marked single subunit corresponding to the above 3D structure on the cell membrane, including the PAS domain at the N-terminal and the C-terminal cyclic nucleotide binding domain (cNBD), transmembrane PD and VSD, as well as the main blocking sites Y652, F656 for specific cardiotoxicity drugs and F627 involving inactivation (D).

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  FIGURE 3. hERG channel gating. The channel has three states: closed, open and inactivated. Schematic diagram of the hERG channel gating scheme, indicating that the state transition between closed and open states is slower than the state transition between open and inactive states. The selectivity filter (SF), located in the central cavity of the pore domain, and the intracellular activation gate (AG) coupling (AG/SF coupling) are thought to participate in different state changes.

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  FIGURE 4. Voltage gating regulation model for hERG channel based on the PAS/cNBD complex. The PAS/cNBD complex plays a central role (blue dotted line) in this model. Previously, the S4-S5 linker was thought to act as a bridge to transform the conformational changes in the voltage-sensing domain (VSD) into physical movement of the pore domain (PD) and then interact with adjacent subunits to regulate the pore gate (green dotted line). A new insight is that the S4-S5 linker cannot act as a bridge (red cross), but S4 of VSD directly interacts with S6 of the same subunit, resulting in a change in the state of S6 followed by opening or closing of the channel gate (red dotted line and arrow).

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  FIGURE 5. Model of VSD relaxation. In the hERG channel, depolarization activates the channel, and then repolarization causes the channel to deactivate and the VSD to enter a relaxed state, resulting in hysteresis. (A) Compared to pH 7.4 (solid line), the acidic pH (dotted line) shortens the hysteresis behavior of the channel, thereby accelerating the deactivation process. (B). Cartoon representation of proposed reconfigurations of S2, S3, and S4 transmembrane domains in the resting, activated, and relaxed states. S4 in VSD undergoes a conformational change from a stable resting state to a relaxed state due to the voltage change. Putative reconfigurations associated with entering a relaxed state may involve the interaction of D509 with the positive external charge of S4. The neutralization of D509 or external protonation is predicted to destabilize the interactions, thereby destroying the relaxed state. Arrows indicate the hypothetical structural rearrangements of the helix during the relaxation process resulting from the interaction of the acidic residues in S2-S3 (C).