Abstract
Influenza viruses are among the most common pathogens that threaten the health of humans and animals worldwide. Various anti-viral therapeutic agents are currently used for treatment and prophylaxis of influenza virus, but the targets of these drugs are easily mutated and result in resistance. Therefore, medications that have broad spectrum coverage are urgently needed to combat with the disease. Since nucleoprotein is regarded as a druggable target due to its conserved sequence and important functions during influenza virus life cycle, numerous studies are focused on this protein in attempts to develop broad-spectrum anti-influenza therapeutics. Recently, a novel small molecule compound, nucleozin, was found to induce large aggregates of nucleoprotein, which in turn caused cessation of virus replication. However, the aggregation-inducing mechanism of nucleozin has not been unveiled. Here we report the crystal structure of nucleoprotein-nucleozin complex at 3 Å resolution, which shows the binding sites of nucleozin at nucleoprotein for the first time. The complex structure reveals how nucleoprotein and nucleozin interact with each other and hence result in nucleoprotein aggregates. The structural information is envisaged to help accelerate the development of anti-influenza therapeutic agents.
Highlights
Influenza is usually acute self-limiting respiratory infection, influenza viruses are among the most common pathogens that threaten the health of humans and animals worldwide
The crystal structure of nucleozin bound H1N1 NP has been solved at a resolution of 3.0 Å and there are six NP molecules assembled into two trimers in the crystallographic asymmetric unit (Fig. 1A,B)
Similar to the reported apo H1N1 NP15 (PDB code 2IQH) and H5N1 NP16 (PDB code 2Q06), each NP molecule in the asymmetric unit folds into three parts, a helical body domain, a helical head domain and a tail loop inserted into its neighboring molecule to form NP trimers
Summary
Influenza is usually acute self-limiting respiratory infection, influenza viruses are among the most common pathogens that threaten the health of humans and animals worldwide. Kao et al identified NP as an anti-influenza drug target using advanced chemical genetics approach, and reported that a novel small molecule named nucleozin could target this protein[13]. Gerritz et al conducted similar research on nucleozin and its analogs, showing that nucleozin and its analogs exert certain inhibitory effect on influenza virus life cycle[14]. They attained the crystal structure of NP in complex with a nucleozin analog through co-crystallization, and found that the binding sites of the nucleozin analog (Compound 3) were formed by a combination of the pockets from two different NP trimers, i.e., Y289/N309 pocket from one trimer and Y52 pocket from the other one. The binding sites have been clearly revealed and the binding model of nucleozin induced NP aggregates is proposed, which may help to understand the unique mechanism of nucleozin-induced NP aggregation at atomic level, and shed new light on discovery of novel drugs targeting NP
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