Mechanism of 150-cavity formation in influenza neuraminidase

被引:119
作者
Amaro, Rommie E. [1 ]
Swift, Robert V. [1 ]
Votapka, Lane [1 ]
Li, Wilfred W.
Walker, Ross C. [2 ]
Bush, Robin M. [3 ]
机构
[1] Univ Calif Irvine, Dept Pharmaceut Sci Comp Sci & Chem, Irvine, CA 92697 USA
[2] Univ Calif San Diego, Dept Chem & Biochem, San Diego Supercomp Ctr, La Jolla, CA 92093 USA
[3] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92697 USA
来源
NATURE COMMUNICATIONS | 2011年 / 2卷
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
MOLECULAR-DYNAMICS; SIMULATION; VIRUS; N1;
D O I
10.1038/ncomms1390
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The recently discovered 150-cavity in the active site of group-1 influenza A neuraminidase (NA) proteins provides a target for rational structure-based drug development to counter the increasing frequency of antiviral resistance in influenza. Surprisingly, the 2009 H1N1 pandemic virus (09N1) neuramidase was crystalized without the 150-cavity characteristic of group-1 NAs. Here we demonstrate, through a total sum of 1.6 mu s of biophysical simulations, that 09N1 NA exists in solution preferentially with an open 150-cavity. Comparison with simulations using avian N1, human N2 and 09N1 with a I149V mutation and an extensive bioinformatics analysis suggests that the conservation of a key salt bridge is crucial in the stabilization of the 150-cavity across both subtypes. This result provides an atomic-level structural understanding of the recent finding that antiviral compounds designed to take advantage of contacts in the 150-cavity can inactivate both 2009 H1N1 pandemic and avian H5N1 viruses.
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页数:7
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