期刊
NATURE COMMUNICATIONS
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1390
关键词
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资金
- National Institutes of Health [1-DP2-OD007237, 1-K22-AI081901, P41 RR08605]
- NSF [NSF1047875]
- National Institute for Computational Science [TG-CHE100128]
- San Diego Supercomputer Center [TG-MCB090110]
- University of California (UC Lab) [09-LR-06-117792]
- National Institute of General Medical Sciences MIDAS [U01-GM076499]
- Office of Advanced Cyberinfrastructure (OAC)
- Direct For Computer & Info Scie & Enginr [1047875] Funding Source: National Science Foundation
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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