Capturing a Flavivirus Pre-Fusion Intermediate

PLoS Pathogens

Richard J. Kuhn¹  Paul R. Chipman²  Bärbel Kaufmann²  Heather A. Holdaway²  Michael S. Diamond²  Daved H. Fremont³  Michael G. Rossmann³  Syd Johnson⁴ 

[1] Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America;Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America;MacroGenics Inc., Rockville, Maryland, United States of America

关键词: West Nile virus;    Virions;    Viral structure;    Lipid bilayer;    Viral entry;    Membrane fusion;    Dengue virus;    Flaviviruses;   

DOI  :  10.1371/journal.ppat.1000672

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

During cell entry of flaviviruses, low endosomal pH triggers the rearrangement of the viral surface glycoproteins to a fusion-active state that allows the release of the infectious RNA into the cytoplasm. In this work, West Nile virus was complexed with Fab fragments of the neutralizing mAb E16 and was subsequently exposed to low pH, trapping the virions in a pre-fusion intermediate state. The structure of the complex was studied by cryo-electron microscopy and provides the first structural glimpse of a flavivirus fusion intermediate near physiological conditions. A radial expansion of the outer protein layer of the virion was observed compared to the structure at pH 8. The resulting ∼60 Å-wide shell of low density between lipid bilayer and outer protein layer is likely traversed by the stem region of the E glycoprotein. By using antibody fragments, we have captured a structural intermediate of a virus that likely occurs during cell entry. The trapping of structural transition states by antibody fragments will be applicable for other processes in the flavivirus life cycle and delineating other cellular events that involve conformational rearrangements.

【 授权许可】

CC BY