Molecular Dynamics Simulations Suggest Possible Activation and Deactivation Pathways in the HERG Channel

Overview

Journal Commun Biol

Specialty Biology

Date 2022 Feb 25

PMID 35210539

Authors

Flavio Costa

Carlo Guardiani

Alberto Giacomello

Affiliations

Soon will be listed here.

Abstract

The elusive activation/deactivation mechanism of hERG is investigated, a voltage-gated potassium channel involved in severe inherited and drug-induced cardiac channelopathies, including the Long QT Syndrome. Firstly, the available structural data are integrated by providing a homology model for the closed state of the channel. Secondly, molecular dynamics combined with a network analysis revealed two distinct pathways coupling the voltage sensor domain with the pore domain. Interestingly, some LQTS-related mutations known to impair the activation/deactivation mechanism are distributed along the identified pathways, which thus suggests a microscopic interpretation of their role. Split channels simulations clarify a surprising feature of this channel, which is still able to gate when a cut is introduced between the voltage sensor domain and the neighboring helix S5. In summary, the presented results suggest possible activation/deactivation mechanisms of non-domain-swapped potassium channels that may aid in biomedical applications.

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References

Trudeau M, Warmke J, Ganetzky B, Robertson G . HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995; 269(5220):92-5. DOI: 10.1126/science.7604285. View

Curran M, Splawski I, Timothy K, Vincent G, Green E, Keating M . A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995; 80(5):795-803. DOI: 10.1016/0092-8674(95)90358-5. View

Sanguinetti M, Tristani-Firouzi M . hERG potassium channels and cardiac arrhythmia. Nature. 2006; 440(7083):463-9. DOI: 10.1038/nature04710. View

Recanatini M, Poluzzi E, Masetti M, Cavalli A, De Ponti F . QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development. Med Res Rev. 2004; 25(2):133-66. DOI: 10.1002/med.20019. View

Butler A, Helliwell M, Zhang Y, Hancox J, Dempsey C . An Update on the Structure of hERG. Front Pharmacol. 2020; 10:1572. PMC: 6992539. DOI: 10.3389/fphar.2019.01572. View

De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N . Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf. 2002; 25(4):263-86. DOI: 10.2165/00002018-200225040-00004. View

Sanguinetti M, Mitcheson J . Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci. 2005; 26(3):119-24. DOI: 10.1016/j.tips.2005.01.003. View

Cavero I, Guillon J, Ballet V, Clements M, Gerbeau J, Holzgrefe H . Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation. J Pharmacol Toxicol Methods. 2016; 81:21-36. DOI: 10.1016/j.vascn.2016.05.012. View

Colatsky T, Fermini B, Gintant G, Pierson J, Sager P, Sekino Y . The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative - Update on progress. J Pharmacol Toxicol Methods. 2016; 81:15-20. DOI: 10.1016/j.vascn.2016.06.002. View

10.

Li J, Shen R, Reddy B, Perozo E, Roux B . Mechanism of C-type inactivation in the hERG potassium channel. Sci Adv. 2021; 7(5). PMC: 7846155. DOI: 10.1126/sciadv.abd6203. View

11.

Wang S, Liu S, Morales M, Strauss H, Rasmusson R . A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J Physiol. 1997; 502 ( Pt 1):45-60. PMC: 1159571. DOI: 10.1111/j.1469-7793.1997.045bl.x. View

12.

Wang W, MacKinnon R . Cryo-EM Structure of the Open Human Ether-à-go-go-Related K Channel hERG. Cell. 2017; 169(3):422-430.e10. PMC: 5484391. DOI: 10.1016/j.cell.2017.03.048. View

13.

Whicher J, MacKinnon R . Structure of the voltage-gated K⁺ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016; 353(6300):664-9. PMC: 5477842. DOI: 10.1126/science.aaf8070. View

14.

Zhang M, Liu J, Tseng G . Gating charges in the activation and inactivation processes of the HERG channel. J Gen Physiol. 2004; 124(6):703-18. PMC: 2234031. DOI: 10.1085/jgp.200409119. View

15.

de la Pena P, Dominguez P, Barros F . Gating mechanism of Kv11.1 (hERG) K channels without covalent connection between voltage sensor and pore domains. Pflugers Arch. 2017; 470(3):517-536. PMC: 5805800. DOI: 10.1007/s00424-017-2093-9. View

16.

Jones S . Commentary: a plausible model. J Gen Physiol. 1999; 114(2):271-5. PMC: 2230645. DOI: 10.1085/jgp.114.2.271. View

17.

Changeux J, Devillers-Thiery A, Chemouilli P . Acetylcholine receptor: an allosteric protein. Science. 1984; 225(4668):1335-45. DOI: 10.1126/science.6382611. View

18.

Guo J, Zhou H . Protein Allostery and Conformational Dynamics. Chem Rev. 2016; 116(11):6503-15. PMC: 5011433. DOI: 10.1021/acs.chemrev.5b00590. View

19.

Papaleo E, Lindorff-Larsen K, De Gioia L . Paths of long-range communication in the E2 enzymes of family 3: a molecular dynamics investigation. Phys Chem Chem Phys. 2012; 14(36):12515-25. DOI: 10.1039/c2cp41224a. View

20.

Ghosh A, Vishveshwara S . A study of communication pathways in methionyl- tRNA synthetase by molecular dynamics simulations and structure network analysis. Proc Natl Acad Sci U S A. 2007; 104(40):15711-6. PMC: 2000407. DOI: 10.1073/pnas.0704459104. View