Unusual architecture of the p7 channel from hepatitis C virus

	Unusual architecture of the p7 channel from hepatitis C virus
	OuYang, B; Xie, SQ; Berardi, MJ; Zhao, XH; Dev, J; Yu, WJ; Sun, B; Chou, JJ
刊名	NATURE
	2013
卷号	498 期号:7455 页码:521-521
通讯作者	Chou, JJ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.,bsun@sibs.ac.cn
英文摘要	The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations(1-4). We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine(2,5), which are potent blockers of the influenza M2 channel(6) and licensed drugs against influenza infections(7). The adamantane derivatives have been used in HCV clinical trials(8), but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	INFLUENZA-A VIRUS ; ION-CHANNEL ; IMINOSUGAR DERIVATIVES ; POLYACRYLAMIDE GELS ; NMR-SPECTROSCOPY ; PROTON CHANNEL ; CHEMICAL-SHIFT ; PROTEIN ; AMANTADINE ; SENSITIVITY
收录类别	SCI
语种	英语
WOS记录号	WOS:000320929400060
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/483]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	OuYang, B,Xie, SQ,Berardi, MJ,et al. Unusual architecture of the p7 channel from hepatitis C virus[J]. NATURE,2013,498(7455):521-521.
APA	OuYang, B.,Xie, SQ.,Berardi, MJ.,Zhao, XH.,Dev, J.,...&Chou, JJ.(2013).Unusual architecture of the p7 channel from hepatitis C virus.NATURE,498(7455),521-521.
MLA	OuYang, B,et al."Unusual architecture of the p7 channel from hepatitis C virus".NATURE 498.7455(2013):521-521.