1 Drug Design Lab., Grad. Sch. of Med. Life Sci., Yokohama City Univ.nucleoprotein and host factor.Structural insights into the interaction between influenza A virus The influenza A virus (IAV) viral genome RNA (vRNA) is packaged into a ribonucleoprotein (RNP) complex that transcribes and replicates. RNPs are formed within the nucleus of infected cells and bind to vRNA, the homotrimeric nuclear protein NP, and RNA polymerase. Therefore, transporting NP into the nucleus is essential for forming functional RNPs. NP binds to the host cell Importin-α5 protein to be transported into the nucleus. We determined the structure of the human Importin-α5/NP complex by electron microscopy at 3.7 Å resolution to elucidate the mechanism of nuclear transport. Our model shows that NP forms a 1:1 complex with Importin-α5, with an intermolecular interface area of approximately 1,120 Ų. Amino acids in the NLS domains interact with Importin-α5 and a few of its amino acids. The NLS2 domain (residues 210-230) interacts with Importin-α5 (residues 480-505) by forming bonds between the polar amino acids Arg221 (NLS2) and Glu485 (Importin-α5). Additionally, the loop region (residues 402-428) involved in NP trimer formation is not mapped and is an unstable region. This is because amino acid residues 450-465 block the entrance to the pocket in the Importin-α5/NP complex formation, structurally hindering trimer formation. Using HeLa cells, we found that the nuclear transport efficiency of the NP monomer mutant R416A is higher than that of the wild type, indicating a stronger tendency for NP to localize in the nucleus. These results suggest a mechanism by which NP forms a 1:1 complex with Importin-α5. This structural information identifies an important binding pocket in the Importin-α5/NP complex that may serve as a promising target for developing antiviral drugs against influenza. ○Haruka Umezawa1 Naito Ishimoto1 Sam-Yong Park153P 023
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