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      An Intrinsically Disordered Region of the Adenovirus Capsid Is Implicated in Neutralization by Human Alpha Defensin 5

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          Abstract

          Human α-defensins are proteins of the innate immune system that suppress viral and bacterial infections by multiple mechanisms including membrane disruption. For viruses that lack envelopes, such as human adenovirus (HAdV), other, less well defined, mechanisms must be involved. A previous structural study on the interaction of an α-defensin, human α-defensin 5 (HD5), with HAdV led to a proposed mechanism in which HD5 stabilizes the vertex region of the capsid and blocks uncoating steps required for infectivity. Studies with virus chimeras comprised of capsid proteins from sensitive and resistant serotypes supported this model. To further characterize the critical binding site, we determined subnanometer resolution cryo-electron microscopy (cryoEM) structures of HD5 complexed with both neutralization-sensitive and -resistant HAdV chimeras. Models were built for the vertex regions of these chimeras with monomeric and dimeric forms of HD5 in various initial orientations. CryoEM guided molecular dynamics flexible fitting (MDFF) was used to restrain the majority of the vertex model in well-defined cryoEM density. The RGD-containing penton base loops of both the sensitive and resistant virus chimeras are predicted to be intrinsically disordered, and little cryoEM density is observed for them. In simulations these loops from the sensitive virus chimera, interact with HD5, bridge the penton base and fiber proteins, and provides significant stabilization with a three-fold increase in the intermolecular nonbonded interactions of the vertex complex. In the case of the resistant virus chimera, simulations revealed fewer bridging interactions and reduced stabilization by HD5. This study implicates a key dynamic region in mediating a stabilizing interaction between a viral capsid and a protein of the innate immune system with potent anti-viral activity.

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          Defensins: antimicrobial peptides of innate immunity.

          Tomas Ganz (2003)
          The production of natural antibiotic peptides has emerged as an important mechanism of innate immunity in plants and animals. Defensins are diverse members of a large family of antimicrobial peptides, contributing to the antimicrobial action of granulocytes, mucosal host defence in the small intestine and epithelial host defence in the skin and elsewhere. This review, inspired by a spate of recent studies of defensins in human diseases and animal models, focuses on the biological function of defensins.
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            Flexible fitting of atomic structures into electron microscopy maps using molecular dynamics.

            A novel method to flexibly fit atomic structures into electron microscopy (EM) maps using molecular dynamics simulations is presented. The simulations incorporate the EM data as an external potential added to the molecular dynamics force field, allowing all internal features present in the EM map to be used in the fitting process, while the model remains fully flexible and stereochemically correct. The molecular dynamics flexible fitting (MDFF) method is validated for available crystal structures of protein and RNA in different conformations; measures to assess and monitor the fitting process are introduced. The MDFF method is then used to obtain high-resolution structures of the E. coli ribosome in different functional states imaged by cryo-EM.
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              PrDOS: prediction of disordered protein regions from amino acid sequence

              PrDOS is a server that predicts the disordered regions of a protein from its amino acid sequence (http://prdos.hgc.jp). The server accepts a single protein amino acid sequence, in either plain text or FASTA format. The prediction system is composed of two predictors: a predictor based on local amino acid sequence information and one based on template proteins. The server combines the results of the two predictors and returns a two-state prediction (order/disorder) and a disorder probability for each residue. The prediction results are sent by e-mail, and the server also provides a web-interface to check the results.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                19 April 2013
                : 8
                : 4
                : e61571
                Affiliations
                [1 ]Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, United States of America
                [2 ]Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States of America
                [3 ]Department of Microbiology, University of Washington, Seattle, Washington, United States of America
                [4 ]Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
                French National Centre for Scientific Research, France
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JGS GRN PLS. Performed the experiments: JWF RK. Analyzed the data: JWF PLS RK. Contributed reagents/materials/analysis tools: JGS GRN. Wrote the paper: JWF JGS GRN PLS.

                Article
                PONE-D-13-07176
                10.1371/journal.pone.0061571
                3631211
                23620768
                81053e7f-1c9e-4a57-bf39-11a7b67ba6a4
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 February 2013
                : 10 March 2013
                Page count
                Pages: 10
                Funding
                This work was funded by the United States National Institutes of Health (NIH)/General Medicine (T32 GM008803) to JWF; National Institute of Allergy and Infectious Diseases (AI081870) to JGS; National Eye Institute (EY11431) to GRN; Heart Lung and Blood Institute (HL54352) to GRN; and National Institute of Allergy and Infectious Diseases (AI042929) to PLS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Biophysics
                Biomacromolecule-Ligand Interactions
                Biophysics Simulations
                Macromolecular Assemblies
                Computational Biology
                Macromolecular Structure Analysis
                Macromolecular Complex Analysis
                Protein Structure
                Biophysic Al Simulations
                Microbiology
                Immunity
                Innate Immunity
                Virology
                Viral Structure
                Host-Pathogen Interaction
                Chemistry
                Computational Chemistry
                Molecular Dynamics

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                Uncategorized

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