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Title: Atomic Level Characterization of the Nonproton Ligand-sensing Domain of ASIC3 Channels
Author: Yu, Ye ; Li, Wei-Guang ; Chen, Zhi ; Cao, Hui ; Yang, Huaiyu ; Jiang, Hualiang ; Xu, Tian-Le(徐天乐)
Source: JOURNAL OF BIOLOGICAL CHEMISTRY
Issued Date: 2011
Volume: 286, Issue:28, Pages:24996-25006
Keyword: ION-CHANNEL ; MOLECULAR-DYNAMICS ; EXTRACELLULAR DOMAIN ; NEURONS ; PORE ; 1A ; DESENSITIZATION ; ION-CHANNEL-1 ; MODULATION ; ACIDOSIS
Subject: Biochemistry & Molecular Biology
Corresponding Author: Jiang, HL (reprint author), 555 Zu Chong Zhi Rd,Zhang Jiang Hi Tech Pk, Shanghai 201203, Peoples R China,hljiang@mail.shcnc.ac.cn
English Abstract: Acid-sensing ion channels (ASICs) are known to be primarily activated by extracellular protons. Recently, we characterized a novel nonproton ligand (2-guanidine-4-methylquinazoline, GMQ), which activates the ASIC3 channel subtype at neutral pH. Using an interactive computational-experimental approach, here we extend our investigation to delineate the architecture of the GMQ-sensing domain in the ASIC3 channels. We first established a GMQ binding mode and revealed that residues Glu-423, Glu-79, Leu-77, Arg-376, Gln-271, and Gln-269 play key roles in forming the GMQ-sensing domain. We then verified the GMQ binding mode using ab initio calculation and mutagenesis and demonstrated the critical role of the above GMQ-binding residues in the interplay among GMQ, proton, and Ca(2+) in regulating the function of ASIC3. Additionally, we showed that the same residues involved in coordinating GMQ responses are also critical for activation of the ASIC3(E79C) mutant by thiol-reactive compound DTNB. Thus, a range of complementary techniques provide independent evidence for the structural details of the GMQ-sensing domain at atomic level, laying the foundation for further investigations of endogenous nonproton ligands and gating mechanisms of the ASIC3 channels.
Indexed Type: SCI
Language: 英语
Content Type: 期刊论文
URI: http://ir.sibs.ac.cn/handle/331001/1533
Appears in Collections:神经所(总)_期刊论文

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Yu, Ye; Li, Wei-Guang; Chen, Zhi; Cao, Hui; Yang, Huaiyu; Jiang, Hualiang; Xu, Tian-Le.Atomic Level Characterization of the Nonproton Ligand-sensing Domain of ASIC3 Channels,JOURNAL OF BIOLOGICAL CHEMISTRY,2011,286(28):24996-25006
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