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  • 1
    Publication Date: 2013-11-02
    Description: Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site O, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site O when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site O-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461862/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461862/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLellan, Jason S -- Chen, Man -- Joyce, M Gordon -- Sastry, Mallika -- Stewart-Jones, Guillaume B E -- Yang, Yongping -- Zhang, Baoshan -- Chen, Lei -- Srivatsan, Sanjay -- Zheng, Anqi -- Zhou, Tongqing -- Graepel, Kevin W -- Kumar, Azad -- Moin, Syed -- Boyington, Jeffrey C -- Chuang, Gwo-Yu -- Soto, Cinque -- Baxa, Ulrich -- Bakker, Arjen Q -- Spits, Hergen -- Beaumont, Tim -- Zheng, Zizheng -- Xia, Ningshao -- Ko, Sung-Youl -- Todd, John-Paul -- Rao, Srinivas -- Graham, Barney S -- Kwong, Peter D -- ZIA AI005024-11/Intramural NIH HHS/ -- ZIA AI005061-10/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 Nov 1;342(6158):592-8. doi: 10.1126/science.1243283.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24179220" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Neutralizing/immunology ; Antigens, Viral/*chemistry/genetics/immunology ; Crystallography, X-Ray ; Cysteine/chemistry/genetics ; Glycoproteins/*chemistry/genetics/immunology ; Humans ; Macaca ; Mice ; Protein Engineering ; Protein Multimerization ; Protein Stability ; Protein Structure, Tertiary ; Respiratory Syncytial Virus Infections/*prevention & control ; Respiratory Syncytial Virus Vaccines/*chemistry ; Vaccination ; Viral Fusion Proteins/*chemistry/genetics/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-04-27
    Description: The prefusion state of respiratory syncytial virus (RSV) fusion (F) glycoprotein is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab. The cocrystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed D25 to lock F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to the newly identified site of vulnerability, which we named antigenic site O. These studies should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459498/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459498/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLellan, Jason S -- Chen, Man -- Leung, Sherman -- Graepel, Kevin W -- Du, Xiulian -- Yang, Yongping -- Zhou, Tongqing -- Baxa, Ulrich -- Yasuda, Etsuko -- Beaumont, Tim -- Kumar, Azad -- Modjarrad, Kayvon -- Zheng, Zizheng -- Zhao, Min -- Xia, Ningshao -- Kwong, Peter D -- Graham, Barney S -- ZIA AI005024-11/Intramural NIH HHS/ -- ZIA AI005061-10/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 May 31;340(6136):1113-7. doi: 10.1126/science.1234914. Epub 2013 Apr 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mclellanja@niaid.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23618766" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Neutralizing/chemistry/*immunology ; Crystallography, X-Ray ; Female ; Glycoproteins/chemistry/*immunology ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Neutralization Tests ; Palivizumab ; Protein Conformation ; Protein Multimerization ; Respiratory Syncytial Virus Vaccines/chemistry/*immunology ; Respiratory Syncytial Viruses/*immunology/physiology ; Viral Fusion Proteins/chemistry/*immunology ; Virus Internalization
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2015-09-22
    Description: Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 A. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ge, Jingpeng -- Li, Wanqiu -- Zhao, Qiancheng -- Li, Ningning -- Chen, Maofei -- Zhi, Peng -- Li, Ruochong -- Gao, Ning -- Xiao, Bailong -- Yang, Maojun -- England -- Nature. 2015 Nov 5;527(7576):64-9. doi: 10.1038/nature15247. Epub 2015 Sep 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences or Medicine, Tsinghua University, Beijing 100084, China. ; Ministry of Education, Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26390154" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/metabolism ; *Cryoelectron Microscopy ; Electric Conductivity ; Ion Channel Gating ; Ion Channels/*chemistry/metabolism/*ultrastructure ; Mice ; Models, Molecular ; Pliability ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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