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      Pre-fusion structure of a human coronavirus spike protein

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          Abstract

          A 4.0 Å resolution cryo-electron microscopy structure of the pre-fusion form of the trimeric spike from the human coronavirus HKU1 provides insight into how the spike protein mediates host-cell attachment and membrane fusion.

          Supplementary information

          The online version of this article (doi:10.1038/nature17200) contains supplementary material, which is available to authorized users.

          Coronavirus spike structure

          Coronaviruses are responsible for respiratory infections worldwide, many of them mild, but also including severe pneumonia and the recent SARS and MERS outbreaks. The entry of coronaviruses into cells is mediated by the virus glycoprotein spike trimer, which contains the receptor-binding domain, as well as membrane fusion domains. Two papers published in this issue of Nature provide high-resolution (4Å) cryo-electron microscopy structures of pre-fusion coronavirus spike trimers. David Veesler and colleagues studied the trimer from murine hepatitis virus; Andrew Ward and colleagues used the human betacoronavirus HKU1, a cause of mild respiratory disease. The structures reveal mechanistic insights into the viral fusion process and architectural similarities to paramyxovirus F proteins, suggesting that these fusion proteins may have evolved from a distant common ancestor.

          Supplementary information

          The online version of this article (doi:10.1038/nature17200) contains supplementary material, which is available to authorized users.

          Abstract

          HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease 1 , and is related to the zoonotic SARS 2 and MERS 3 betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein 4 , which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 Å resolution structure of the trimeric HKU1 S protein determined using single-particle cryo-electron microscopy. In the pre-fusion conformation, the receptor-binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens.

          Supplementary information

          The online version of this article (doi:10.1038/nature17200) contains supplementary material, which is available to authorized users.

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          Most cited references 15

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          Comparative Protein Structure Modeling Using MODELLER.

          Functional characterization of a protein sequence is one of the most frequent problems in biology. This task is usually facilitated by accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described. Curr. Protoc. Bioinform. 47:5.6.1-5.6.32. © 2014 by John Wiley & Sons, Inc. Copyright © 2014 John Wiley & Sons, Inc.
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            Accurate determination of local defocus and specimen tilt in electron microscopy

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              Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution.

              The haemagglutinin glycoprotein of influenza virus is a trimer comprising two structurally distinct regions: a triple-stranded coiled-coil of alpha-helices extends 76 A from the membrane and a globular region of antiparallel beta-sheet, which contains the receptor binding site and the variable antigenic determinants, is positioned on top of this stem. Each subunit has an unusual loop-like topology, starting at the membrane, extending 135 A distally and folding back to enter the membrane.
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                Author and article information

                Contributors
                Jason.S.McLellan@Dartmouth.edu
                ABWard@Scripps.edu
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                2 March 2016
                2016
                : 531
                : 7592
                : 118-121
                Affiliations
                [1 ]GRID grid.214007.0, ISNI 0000000122199231, Department of Integrative Structural and Computational Biology, , The Scripps Research Institute, ; 10550 North Torrey Pines Road, La Jolla, 92037 California USA
                [2 ]GRID grid.254880.3, ISNI 0000 0001 2179 2404, Department of Biochemistry, , Geisel School of Medicine at Dartmouth, ; Hanover, 03755 New Hampshire USA
                [3 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Viral Pathogenesis Laboratory, National Institute of Allergy and Infectious Diseases, ; Building 40, Room 2502, 40 Convent Drive, Bethesda, 20892 Maryland USA
                [4 ]GRID grid.412603.2, ISNI 0000 0004 0634 1084, Present Address: † Present address: Biomedical Research Center, Qatar University, QU-NRC, Zone 5, Room D130, Doha, Qatar., ; ,
                Article
                BFnature17200
                10.1038/nature17200
                4860016
                26935699
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2016

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2016

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                cryoelectron microscopy, sars virus

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