Crystal Structure of the Hendra Virus Attachment G Glycoprotein Bound to a Potent Cross-Reactive Neutralizing Human Monoclonal Antibody

PLoS Pathogens

Christopher C. Broder¹  Zhongyu Zhu²  Yan Xu²  Deborah L. Fusco³  Dimiter S. Dimitrov⁴  Heinz Feldmann⁴  Blair L. DeBuysscher⁵  Kimberly A. Bishop-Lilly⁵  Regina Z. Cer⁶  Vishwesh Mokashi⁶  Dimitar B. Nikolov⁶  Yee-Peng Chan⁷  Barry Rockx⁸  Kai Xu⁹  Truong Luu⁹  Yihu Xie⁹ 

[1] Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada;Department of Microbiology and Immunology, Uniformed Services University, Bethesda, Maryland, United States of America;Division of Biological Sciences and the University of Montana, Missoula, Montana, United States of America;Henry M. Jackson Foundation, Bethesda, Maryland, United States of America;Laboratory of Virology, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, United States of America;Naval Medical Research Center, NMRC-Frederick, Fort Detrick, Maryland, United States of America;Protein Interactions Group, CCRNP, CCR, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland, United States of America;Sealy Center for Vaccine Development, Departments of Pathology and Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America;Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America

关键词: Crystal structure;    Antibodies;    Glycoproteins;    Henipavirus;    Sequence alignment;    Virus glycoproteins;    Hendra virus;    Viral structure;   

DOI  :  10.1371/journal.ppat.1003684

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The henipaviruses, represented by Hendra (HeV) and Nipah (NiV) viruses are highly pathogenic zoonotic paramyxoviruses with uniquely broad host tropisms responsible for repeated outbreaks in Australia, Southeast Asia, India and Bangladesh. The high morbidity and mortality rates associated with infection and lack of licensed antiviral therapies make the henipaviruses a potential biological threat to humans and livestock. Henipavirus entry is initiated by the attachment of the G envelope glycoprotein to host cell membrane receptors. Previously, henipavirus-neutralizing human monoclonal antibodies (hmAb) have been isolated using the HeV-G glycoprotein and a human naïve antibody library. One cross-reactive and receptor-blocking hmAb (m102.4) was recently demonstrated to be an effective post-exposure therapy in two animal models of NiV and HeV infection, has been used in several people on a compassionate use basis, and is currently in development for use in humans. Here, we report the crystal structure of the complex of HeV-G with m102.3, an m102.4 derivative, and describe NiV and HeV escape mutants. This structure provides detailed insight into the mechanism of HeV and NiV neutralization by m102.4, and serves as a blueprint for further optimization of m102.4 as a therapeutic agent and for the development of entry inhibitors and vaccines.

【 授权许可】

CC BY