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  • 1
    Publication Date: 2014-02-07
    Description: Vaccines prevent infectious disease largely by inducing protective neutralizing antibodies against vulnerable epitopes. Several major pathogens have resisted traditional vaccine development, although vulnerable epitopes targeted by neutralizing antibodies have been identified for several such cases. Hence, new vaccine design methods to induce epitope-specific neutralizing antibodies are needed. Here we show, with a neutralization epitope from respiratory syncytial virus, that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies. These scaffolds represent promising leads for the research and development of a human respiratory syncytial virus vaccine needed to protect infants, young children and the elderly. More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets, including antigenically highly variable pathogens such as human immunodeficiency virus and influenza.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260937/" 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/PMC4260937/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Correia, Bruno E -- Bates, John T -- Loomis, Rebecca J -- Baneyx, Gretchen -- Carrico, Chris -- Jardine, Joseph G -- Rupert, Peter -- Correnti, Colin -- Kalyuzhniy, Oleksandr -- Vittal, Vinayak -- Connell, Mary J -- Stevens, Eric -- Schroeter, Alexandria -- Chen, Man -- Macpherson, Skye -- Serra, Andreia M -- Adachi, Yumiko -- Holmes, Margaret A -- Li, Yuxing -- Klevit, Rachel E -- Graham, Barney S -- Wyatt, Richard T -- Baker, David -- Strong, Roland K -- Crowe, James E Jr -- Johnson, Philip R -- Schief, William R -- 1R01AI102766-01A1/AI/NIAID NIH HHS/ -- 1UM1AI100663/AI/NIAID NIH HHS/ -- 2T32GM007270/GM/NIGMS NIH HHS/ -- 5R21AI088554/AI/NIAID NIH HHS/ -- P01 AI094419/AI/NIAID NIH HHS/ -- P01AI094419/AI/NIAID NIH HHS/ -- P30 AI036214/AI/NIAID NIH HHS/ -- P30 AI045008/AI/NIAID NIH HHS/ -- P30AI36214/AI/NIAID NIH HHS/ -- R01 AI102766/AI/NIAID NIH HHS/ -- R21 AI088554/AI/NIAID NIH HHS/ -- T32 CA080416/CA/NCI NIH HHS/ -- T32 GM007270/GM/NIGMS NIH HHS/ -- T32CA080416/CA/NCI NIH HHS/ -- U54 AI 005714/AI/NIAID NIH HHS/ -- U54 AI057141/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):201-6. doi: 10.1038/nature12966. Epub 2014 Feb 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] PhD Program in Computational Biology, Instituto Gulbenkian Ciencia and Instituto de Tecnologia Quimica e Biologica, Universidade Nova de Lisboa, Oeiras 2780-157, Portugal [3] Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. ; The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. ; The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [3] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [4] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA [2]. ; 1] Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA [2] IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California 92037, USA [3] Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] The Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pathology, Microbiology and Immunology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA [3] Department of Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499818" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Antibodies, Monoclonal/analysis/immunology ; Antibodies, Neutralizing/analysis/immunology ; Antibodies, Viral/analysis/immunology ; Antigens, Viral/chemistry/immunology ; Crystallography, X-Ray ; *Drug Design ; Enzyme-Linked Immunosorbent Assay ; Epitopes/*chemistry/*immunology ; Macaca mulatta/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Neutralization Tests ; Protein Conformation ; *Protein Stability ; Respiratory Syncytial Virus Vaccines/*chemistry/*immunology ; Respiratory Syncytial Viruses/chemistry/immunology
    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: 2011-10-25
    Description: The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Azoitei, Mihai L -- Correia, Bruno E -- Ban, Yih-En Andrew -- Carrico, Chris -- Kalyuzhniy, Oleksandr -- Chen, Lei -- Schroeter, Alexandria -- Huang, Po-Ssu -- McLellan, Jason S -- Kwong, Peter D -- Baker, David -- Strong, Roland K -- Schief, William R -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Oct 21;334(6054):373-6. doi: 10.1126/science.1209368.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22021856" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Amino Acid Motifs ; Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/immunology/metabolism ; Antibodies, Neutralizing/*chemistry/*immunology/metabolism ; Antibody Affinity ; Antibody Specificity ; Antigens, CD4/metabolism ; Computational Biology ; Computer Simulation ; Crystallography, X-Ray ; Epitopes/immunology ; HIV Antibodies/chemistry/*immunology/metabolism ; HIV Envelope Protein gp120/*chemistry/*immunology/metabolism ; Models, Molecular ; Molecular Mimicry ; Molecular Sequence Data ; Mutagenesis ; Protein Conformation ; *Protein Engineering ; Protein Interaction Domains and Motifs ; Surface Plasmon Resonance
    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: 2011-08-23
    Description: Proteins are inherently plastic molecules, whose function often critically depends on excursions between different molecular conformations (conformers). However, a rigorous understanding of the relation between a protein's structure, dynamics and function remains elusive. This is because many of the conformers on its energy landscape are only transiently formed and marginally populated (less than a few per cent of the total number of molecules), so that they cannot be individually characterized by most biophysical tools. Here we study a lysozyme mutant from phage T4 that binds hydrophobic molecules and populates an excited state transiently (about 1 ms) to about 3% at 25 degrees C (ref. 5). We show that such binding occurs only via the ground state, and present the atomic-level model of the 'invisible', excited state obtained using a combined strategy of relaxation-dispersion NMR (ref. 6) and CS-Rosetta model building that rationalizes this observation. The model was tested using structure-based design calculations identifying point mutants predicted to stabilize the excited state relative to the ground state. In this way a pair of mutations were introduced, inverting the relative populations of the ground and excited states and altering function. Our results suggest a mechanism for the evolution of a protein's function by changing the delicate balance between the states on its energy landscape. More generally, they show that our approach can generate and validate models of excited protein states.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706084/" 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/PMC3706084/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bouvignies, Guillaume -- Vallurupalli, Pramodh -- Hansen, D Flemming -- Correia, Bruno E -- Lange, Oliver -- Bah, Alaji -- Vernon, Robert M -- Dahlquist, Frederick W -- Baker, David -- Kay, Lewis E -- R01 GM092802/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Aug 21;477(7362):111-4. doi: 10.1038/nature10349.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics, The University of Toronto, Toronto, Ontario M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21857680" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage T4/*enzymology/*genetics ; Evolution, Molecular ; Hydrophobic and Hydrophilic Interactions ; Ligands ; *Models, Molecular ; Muramidase/*chemistry/*genetics ; *Mutation ; Protein Binding ; Temperature
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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