Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.
Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.
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DOI：
10.1002/prot.22815
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发表时间：
2010-11-01
影响因子：
2.9
通讯作者：
Noskov, Sergei Yu.
中科院分区：
文献类型：
--
作者：
Subbotina, Julia;Yarov-Yarovoy, Vladimir;Lees-Miller, James;Durdagi, Serdar;Guo, Jiqing;Duff, Henry J.;Noskov, Sergei Yu.
The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene, lead to one form of the Long QT Syndrome in humans (LQTS). 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 has been a key target in molecular cardiology and pharmacology for the last decade. While 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 trans-membrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. While 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 to that established by toxin foot-printing and NMR studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed.
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影响因子：
64.8
作者：
Long, Stephen B.;Tao, Xiao;MacKinnon, Roderick
通讯作者：
MacKinnon, Roderick
影响因子：
5.5
作者：
Jiang, M;Zhang, M;Tseng, GN
通讯作者：
Tseng, GN
影响因子：
3.4
作者：
Lees-Miller, James P.;Subbotina, Julia O.;Duff, Henry J.
通讯作者：
Duff, Henry J.
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B
影响因子：
4.3
作者：
Bjelkmar, Par;Niemela, Perttu S.;Vattulainen, Ilpo;Lindahl, Erik
通讯作者：
Lindahl, Erik