Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations

Julia Subbotina, Vladimir Yarov-Yarovoy, James Lees-Miller, Serdar Durdagi, Jiqing Guo, Henry J. Duff, Sergei Yu Noskov

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene lead to one form of the Long QT Syndrome (LQTS) in humans. Promiscuous binding of drugs to hERG1 is known to alter the structure/function of the channel leading to an acquired form of the LQTS. Expectably, creation and validation of reliable 3D model of the channel have been a key target in molecular cardiology and pharmacology for the last decade. Although many models were built, they all were limited to pore domain. In this work, a full model of the hERG1 channel is developed which includes all transmembrane segments. We tested a template-driven denovo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. Although backbone templates for the homology modeled parts of the pore and voltage sensors were based on the available structures of KvAP, Kv1.2 and Kv1.2-Kv2.1 chimera channels, the missing parts are modeled de-novo. The impact of several alignments on the structure of the S4 helix in the voltage-sensing domain was also tested. Herein, final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. These structural elements include salt bridges and close contacts in the voltage-sensor domain; and the topology of the extracellular S5-pore linker compared with that established by toxin footprinting and nuclear magnetic resonance studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed.

Original languageEnglish (US)
Pages (from-to)2922-2934
Number of pages13
JournalProteins: Structure, Function and Bioinformatics
Volume78
Issue number14
DOIs
StatePublished - Nov 1 2010
Externally publishedYes

Keywords

  • De-novo design
  • HERG1 channel
  • Mechanism
  • Proteindrug interactions

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

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