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About the Authors:
Martin K. Safo
* E-mail: [email protected] (MKS); [email protected] (HX)
Affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, United States of America
Faik N. Musayev
Affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, United States of America
Philip D. Mosier
Affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, United States of America
Qibing Zhou
Affiliation: Institute of Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China
Hang Xie
* E-mail: [email protected] (MKS); [email protected] (HX)
Affiliation: Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, United States of America
Umesh R. Desai
Affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, United States of America
Introduction
The matrix protein 1 (M1) of the influenza A virus is a 252-amino acid protein [1], comprised of an N-terminal domain (165 amino acids; N1–165-domain) and a C-terminal domain (87 amino acids; C166–252-domain), and plays an essential role in structural integrity, replication and budding of the virus. In the mature virion, M1 stabilizes the two major viral surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) by forming a matrix layer underneath the lipid bilayer of the viral envelope [2]. M1 also directly interacts with viral ribonucleoprotein (vRNP) consisting of viral RNA (vRNA), RNA polymerases and RNA-binding nucleoprotein (NP) and mediates the import of vRNP for vRNA synthesis in the nucleus of infected cells. Most of these functions are believed to be executed via the 18 kDa N1–165-domain of M1 involving the positively charged nuclear localization signal (NLS) motif 101RKLKR105 and other basic residues adjacent to the NLS [3]–[11].
Previous structural studies on the truncated N1–165-domain have focused on either low pH (pH∼4.5) [4], [12], a condition similar to endosome acidification after virus particles are internalized [13], or neutral pH resembling the cytoplasmic environment...