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  • 1
    Publication Date: 2014-10-09
    Description: The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 A resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348022/" 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/PMC4348022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pancera, Marie -- Zhou, Tongqing -- Druz, Aliaksandr -- Georgiev, Ivelin S -- Soto, Cinque -- Gorman, Jason -- Huang, Jinghe -- Acharya, Priyamvada -- Chuang, Gwo-Yu -- Ofek, Gilad -- Stewart-Jones, Guillaume B E -- Stuckey, Jonathan -- Bailer, Robert T -- Joyce, M Gordon -- Louder, Mark K -- Tumba, Nancy -- Yang, Yongping -- Zhang, Baoshan -- Cohen, Myron S -- Haynes, Barton F -- Mascola, John R -- Morris, Lynn -- Munro, James B -- Blanchard, Scott C -- Mothes, Walther -- Connors, Mark -- Kwong, Peter D -- AI0678501/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P01 GM056550/GM/NIGMS NIH HHS/ -- P01-GM56550/GM/NIGMS NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- R01 GM098859/GM/NIGMS NIH HHS/ -- R01-GM098859/GM/NIGMS NIH HHS/ -- R21 AI100696/AI/NIAID NIH HHS/ -- R21-AI100696/AI/NIAID NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- ZIA AI005023-13/Intramural NIH HHS/ -- ZIA AI005024-13/Intramural NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa. ; Departments of Medicine, Epidemiology, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Duke University Human Vaccine Institute, Departments of Medicine, Surgery, Pediatrics and Immunology, Duke University School of Medicine, and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery at Duke University, Durham, North Carolina 27710, USA. ; 1] Center for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Sandringham, Johannesburg 2131, South Africa [2] University of the Witwatersrand, Braamfontein, Johannesburg 2000, South Africa [3] Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban 4041, South Africa. ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut 06536, USA. ; Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25296255" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Sequence ; Antibodies, Neutralizing/immunology ; Cohort Studies ; Crystallography, X-Ray ; Genetic Variation ; Glycosylation ; HIV Antibodies/immunology ; HIV Envelope Protein gp120/*chemistry/genetics/*immunology ; HIV Envelope Protein gp41/*chemistry/genetics/*immunology ; HIV Infections/immunology ; Humans ; Immune Evasion ; Membrane Fusion ; Models, Molecular ; Molecular Sequence Data ; Polysaccharides/chemistry/immunology ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/genetics/immunology ; Structural Homology, Protein ; Virus Internalization
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-05-14
    Description: The HIV-1 fusion peptide, comprising 15 to 20 hydrophobic residues at the N terminus of the Env-gp41 subunit, is a critical component of the virus-cell entry machinery. Here, we report the identification of a neutralizing antibody, N123-VRC34.01, which targets the fusion peptide and blocks viral entry by inhibiting conformational changes in gp120 and gp41 subunits of Env required for entry. Crystal structures of N123-VRC34.01 liganded to the fusion peptide, and to the full Env trimer, revealed an epitope consisting of the N-terminal eight residues of the gp41 fusion peptide and glycan N88 of gp120, and molecular dynamics showed that the N-terminal portion of the fusion peptide can be solvent-exposed. These results reveal the fusion peptide to be a neutralizing antibody epitope and thus a target for vaccine design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kong, Rui -- Xu, Kai -- Zhou, Tongqing -- Acharya, Priyamvada -- Lemmin, Thomas -- Liu, Kevin -- Ozorowski, Gabriel -- Soto, Cinque -- Taft, Justin D -- Bailer, Robert T -- Cale, Evan M -- Chen, Lei -- Choi, Chang W -- Chuang, Gwo-Yu -- Doria-Rose, Nicole A -- Druz, Aliaksandr -- Georgiev, Ivelin S -- Gorman, Jason -- Huang, Jinghe -- Joyce, M Gordon -- Louder, Mark K -- Ma, Xiaochu -- McKee, Krisha -- O'Dell, Sijy -- Pancera, Marie -- Yang, Yongping -- Blanchard, Scott C -- Mothes, Walther -- Burton, Dennis R -- Koff, Wayne C -- Connors, Mark -- Ward, Andrew B -- Kwong, Peter D -- Mascola, John R -- P01GM56550/GM/NIGMS NIH HHS/ -- R01GM079238/GM/NIGMS NIH HHS/ -- R01GM116654/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2016 May 13;352(6287):828-33. doi: 10.1126/science.aae0474.〈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. ; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. ; HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA. ; Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10021, USA. ; Department of Immunology and Microbial Science, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02142, USA. ; International AIDS Vaccine Initiative, New York, NY 10038, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. pdkwong@nih.gov jmascola@nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27174988" target="_blank"〉PubMed〈/a〉
    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: 2011-11-25
    Description: Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded beta-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which-with PG9-involves a site of vulnerability comprising just two glycans and a strand.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406929/" 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/PMC3406929/" 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 -- Pancera, Marie -- Carrico, Chris -- Gorman, Jason -- Julien, Jean-Philippe -- Khayat, Reza -- Louder, Robert -- Pejchal, Robert -- Sastry, Mallika -- Dai, Kaifan -- O'Dell, Sijy -- Patel, Nikita -- Shahzad-ul-Hussan, Syed -- Yang, Yongping -- Zhang, Baoshan -- Zhou, Tongqing -- Zhu, Jiang -- Boyington, Jeffrey C -- Chuang, Gwo-Yu -- Diwanji, Devan -- Georgiev, Ivelin -- Kwon, Young Do -- Lee, Doyung -- Louder, Mark K -- Moquin, Stephanie -- Schmidt, Stephen D -- Yang, Zhi-Yong -- Bonsignori, Mattia -- Crump, John A -- Kapiga, Saidi H -- Sam, Noel E -- Haynes, Barton F -- Burton, Dennis R -- Koff, Wayne C -- Walker, Laura M -- Phogat, Sanjay -- Wyatt, Richard -- Orwenyo, Jared -- Wang, Lai-Xi -- Arthos, James -- Bewley, Carole A -- Mascola, John R -- Nabel, Gary J -- Schief, William R -- Ward, Andrew B -- Wilson, Ian A -- Kwong, Peter D -- R01 AI033292/AI/NIAID NIH HHS/ -- R01 AI084817/AI/NIAID NIH HHS/ -- RR017573/RR/NCRR NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 23;480(7377):336-43. doi: 10.1038/nature10696.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22113616" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/chemistry/immunology ; Amino Acid Motifs ; Amino Acid Sequence ; Antibodies, Neutralizing/chemistry/*immunology ; Antibody Affinity/immunology ; Antibody Specificity/*immunology ; Antigen-Antibody Complex/chemistry/immunology ; Binding Sites, Antibody/immunology ; Conserved Sequence ; Crystallography, X-Ray ; Epitopes/chemistry/immunology ; Glycopeptides/chemistry/immunology ; Glycosylation ; HIV Antibodies/chemistry/*immunology ; HIV Envelope Protein gp120/*chemistry/*immunology ; HIV-1/*chemistry/*immunology ; Hydrogen Bonding ; Immune Evasion ; Models, Molecular ; Molecular Sequence Data ; Polysaccharides/chemistry/immunology ; Protein Structure, Quaternary ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2013-05-11
    Description: Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1-neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined "neutralization fingerprints" for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1-infected donors and a chimeric siman-human immunodeficiency virus-infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Georgiev, Ivelin S -- Doria-Rose, Nicole A -- Zhou, Tongqing -- Kwon, Young Do -- Staupe, Ryan P -- Moquin, Stephanie -- Chuang, Gwo-Yu -- Louder, Mark K -- Schmidt, Stephen D -- Altae-Tran, Han R -- Bailer, Robert T -- McKee, Krisha -- Nason, Martha -- O'Dell, Sijy -- Ofek, Gilad -- Pancera, Marie -- Srivatsan, Sanjay -- Shapiro, Lawrence -- Connors, Mark -- Migueles, Stephen A -- Morris, Lynn -- Nishimura, Yoshiaki -- Martin, Malcolm A -- Mascola, John R -- Kwong, Peter D -- U19 AI51794/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 May 10;340(6133):751-6. doi: 10.1126/science.1233989.〈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/23661761" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Neutralizing/blood/*immunology ; Epitope Mapping ; HIV Antibodies/blood/*immunology ; HIV Infections/blood/*immunology ; HIV-1/*immunology/isolation & purification ; Humans ; Immunodominant Epitopes/chemistry/immunology ; Macaca ; Neutralization Tests ; Protein Conformation ; Serum/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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  • 5
    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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  • 6
    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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  • 7
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    American Association for the Advancement of Science (AAAS)
    In: Science
    Publication Date: 2018-09-07
    Description: Mutations in two genes, PKD1 and PKD2 , account for most cases of autosomal dominant polycystic kidney disease, one of the most common monogenetic disorders. Here we report the 3.6-angstrom cryo–electron microscopy structure of truncated human PKD1-PKD2 complex assembled in a 1:3 ratio. PKD1 contains a voltage-gated ion channel (VGIC) fold that interacts with PKD2 to form the domain-swapped, yet noncanonical, transient receptor potential (TRP) channel architecture. The S6 helix in PKD1 is broken in the middle, with the extracellular half, S6a, resembling pore helix 1 in a typical TRP channel. Three positively charged, cavity-facing residues on S6b may block cation permeation. In addition to the VGIC, a five–transmembrane helix domain and a cytosolic PLAT domain were resolved in PKD1. The PKD1-PKD2 complex structure establishes a framework for dissecting the function and disease mechanisms of the PKD proteins.
    Keywords: Biochemistry, Online Only
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    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2013-04-05
    Description: Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637846/" 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/PMC3637846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liao, Hua-Xin -- Lynch, Rebecca -- Zhou, Tongqing -- Gao, Feng -- Alam, S Munir -- Boyd, Scott D -- Fire, Andrew Z -- Roskin, Krishna M -- Schramm, Chaim A -- Zhang, Zhenhai -- Zhu, Jiang -- Shapiro, Lawrence -- NISC Comparative Sequencing Program -- Mullikin, James C -- Gnanakaran, S -- Hraber, Peter -- Wiehe, Kevin -- Kelsoe, Garnett -- Yang, Guang -- Xia, Shi-Mao -- Montefiori, David C -- Parks, Robert -- Lloyd, Krissey E -- Scearce, Richard M -- Soderberg, Kelly A -- Cohen, Myron -- Kamanga, Gift -- Louder, Mark K -- Tran, Lillian M -- Chen, Yue -- Cai, Fangping -- Chen, Sheri -- Moquin, Stephanie -- Du, Xiulian -- Joyce, M Gordon -- Srivatsan, Sanjay -- Zhang, Baoshan -- Zheng, Anqi -- Shaw, George M -- Hahn, Beatrice H -- Kepler, Thomas B -- Korber, Bette T M -- Kwong, Peter D -- Mascola, John R -- Haynes, Barton F -- AI067854/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):469-76. doi: 10.1038/nature12053. Epub 2013 Apr 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Duke University Human Vaccine Institute, Departments of Medicine and Immunology, Duke University School of Medicine, Durham, North Carolina 27710, USA. hliao@duke.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552890" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/immunology ; Africa ; Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/genetics/immunology ; Antibodies, Neutralizing/*chemistry/genetics/*immunology ; Antigens, CD4/chemistry/immunology ; Cell Lineage ; Cells, Cultured ; Clone Cells/cytology ; Cross Reactions/immunology ; Crystallography, X-Ray ; Epitopes/chemistry/immunology ; *Evolution, Molecular ; HIV Antibodies/*chemistry/genetics/*immunology ; HIV Envelope Protein gp120/chemistry/genetics/immunology/metabolism ; HIV-1/*chemistry/classification/*immunology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neutralization Tests ; Phylogeny ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2011-08-13
    Description: Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516815/" 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/PMC3516815/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Xueling -- Zhou, Tongqing -- Zhu, Jiang -- Zhang, Baoshan -- Georgiev, Ivelin -- Wang, Charlene -- Chen, Xuejun -- Longo, Nancy S -- Louder, Mark -- McKee, Krisha -- O'Dell, Sijy -- Perfetto, Stephen -- Schmidt, Stephen D -- Shi, Wei -- Wu, Lan -- Yang, Yongping -- Yang, Zhi-Yong -- Yang, Zhongjia -- Zhang, Zhenhai -- Bonsignori, Mattia -- Crump, John A -- Kapiga, Saidi H -- Sam, Noel E -- Haynes, Barton F -- Simek, Melissa -- Burton, Dennis R -- Koff, Wayne C -- Doria-Rose, Nicole A -- Connors, Mark -- NISC Comparative Sequencing Program -- Mullikin, James C -- Nabel, Gary J -- Roederer, Mario -- Shapiro, Lawrence -- Kwong, Peter D -- Mascola, John R -- 5U19 AI 067854-06/AI/NIAID NIH HHS/ -- R01 AI033292/AI/NIAID NIH HHS/ -- U19 AI067854/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2011 Sep 16;333(6049):1593-602. doi: 10.1126/science.1207532. Epub 2011 Aug 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, 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/21835983" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines ; Amino Acid Sequence ; Antibodies, Neutralizing/*chemistry/genetics/*immunology/isolation & purification ; Antibody Affinity ; Antibody Specificity ; Antigens, CD4/metabolism ; Base Sequence ; Binding Sites ; Binding Sites, Antibody ; Complementarity Determining Regions/genetics ; Crystallography, X-Ray ; Epitopes ; *Evolution, Molecular ; Genes, Immunoglobulin Heavy Chain ; HIV Antibodies/*chemistry/genetics/*immunology/isolation & purification ; HIV Envelope Protein gp120/chemistry/*immunology/metabolism ; HIV Infections/immunology ; HIV-1/chemistry/*immunology ; High-Throughput Nucleotide Sequencing ; Humans ; Immunoglobulin Fab Fragments/chemistry/immunology ; Immunoglobulin Heavy Chains/chemistry/immunology ; Immunoglobulin J-Chains/genetics ; Immunoglobulin Light Chains/chemistry/immunology ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Sequence Analysis, DNA
    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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  • 10
    Publication Date: 2013-08-31
    Description: The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the beta form of calcium/calmodulin-dependent protein kinase type II (betaCaMKappaIotaIota) was significantly up-regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing beta-, but not alpha-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of betaCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify betaCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932364/" 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/PMC3932364/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Kun -- Zhou, Tao -- Liao, Lujian -- Yang, Zhongfei -- Wong, Catherine -- Henn, Fritz -- Malinow, Roberto -- Yates, John R 3rd -- Hu, Hailan -- P41 GM103533/GM/NIGMS NIH HHS/ -- R01 MH067880/MH/NIMH NIH HHS/ -- R01 MH091119/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2013 Aug 30;341(6149):1016-20. doi: 10.1126/science.1240729.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P R China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23990563" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antidepressive Agents/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & ; inhibitors/*biosynthesis/genetics ; Depressive Disorder, Major/*enzymology/genetics/psychology ; Disease Models, Animal ; Gene Knockdown Techniques ; Habenula/drug effects/*enzymology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/enzymology ; Promoter Regions, Genetic ; Proteomics ; Rats ; Rats, Sprague-Dawley
    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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