{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:39:23Z","timestamp":1791297563706,"version":"4.1.0"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"12","license":[{"start":{"date-parts":[[2020,9,9]],"date-time":"2020-09-09T00:00:00Z","timestamp":1599609600000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM127723"],"award-info":[{"award-number":["R01GM127723"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P41GM111244"],"award-info":[{"award-number":["P41GM111244"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"publisher","award":["KP1605010"],"award-info":[{"award-number":["KP1605010"]}],"id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD012331"],"award-info":[{"award-number":["S10OD012331"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"publisher","award":["DE-SC0012704"],"award-info":[{"award-number":["DE-SC0012704"]}],"id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,3,24]]},"abstract":"<jats:p>\n                    The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85\u03b2 subunit. Here we present the mechanism underlying the molecular recognition of the p85\u03b2 subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85\u03b2 of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1\n                    <jats:sup>ED<\/jats:sup>\n                    ) undergoes a conformational change to bind p85\u03b2. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1\n                    <jats:sup>ED<\/jats:sup>\n                    exists in a dynamic equilibrium between p85\u03b2-binding\u2013competent and \u2013incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1\n                    <jats:sup>ED<\/jats:sup>\n                    proteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85\u03b2. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1\n                    <jats:sup>ED<\/jats:sup>\n                    can result in the faster hijacking of p85\u03b2 compared to Ud NS1\n                    <jats:sup>ED<\/jats:sup>\n                    , although the former has a lower affinity to p85\u03b2 than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1920582117","type":"journal-article","created":{"date-parts":[[2020,3,9]],"date-time":"2020-03-09T20:26:13Z","timestamp":1583785573000},"page":"6550-6558","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":27,"title":["Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6190-6151","authenticated-orcid":false,"given":"Jae-Hyun","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Texas A&amp;M University, College Station, TX 77843;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nowlan","family":"Savage","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingliang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Byrnes","sequence":"additional","affiliation":[{"name":"National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY 11973;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1057-9194","authenticated-orcid":false,"given":"Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"National Synchrotron Light Source II, Brookhaven National Laboratory, Upton, NY 11973;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonmuk","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Texas A&amp;M University, College Station, TX 77843;"},{"name":"Department of Materials Science and Engineering, Texas A&amp;M University, College Station, TX 77843;"},{"name":"Department of Physics and Astronomy, Texas A&amp;M University, College Station, TX 77843;"},{"name":"School of Computational Sciences, Korea Institute for Advanced Study, 02455 Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1815-3107","authenticated-orcid":false,"given":"Pingwei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&amp;M University, College Station, TX 77843;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,3,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"S225","DOI":"10.2105\/AJPH.2008.151944","article-title":"Estimating influenza-associated deaths in the United States","volume":"99","author":"Thompson W. W.","year":"2009","unstructured":"W. W. Thompson ., Estimating influenza-associated deaths in the United States. Am. J. Public Health 99 (suppl. 2), S225\u2013S230 (2009).","journal-title":"Am. J. Public Health"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1172\/JCI44947","article-title":"Virulence determinants of pandemic influenza viruses","volume":"121","author":"Tscherne D. M.","year":"2011","unstructured":"D. M. Tscherne, A. Garc\u00eda-Sastre, Virulence determinants of pandemic influenza viruses. J. Clin. Invest. 121, 6\u201313 (2011).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/nature05181","article-title":"Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus","volume":"443","author":"Kash J. C.","year":"2006","unstructured":"J. C. Kash ., Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature 443, 578\u2013581 (2006).","journal-title":"Nature"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1126\/science.1119392","article-title":"Characterization of the reconstructed 1918 Spanish influenza pandemic virus","volume":"310","author":"Tumpey T. M.","year":"2005","unstructured":"T. M. Tumpey ., Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77\u201380 (2005).","journal-title":"Science"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/9781118636817.ch7","volume-title":"Textbook of Influenza","author":"Krug R. M.","year":"2013","unstructured":"R. M. Krug, A. Garcia-Sastre, \u201cThe NS1 protein: A master regulator of host and viral functions\u201d in Textbook of Influenza, R. G. Webster, A. S. Monto, T. J. Braciale, R. A. Lamb, Eds. (Wiley-Blackwell, ed. 2, 2013), pp. 114\u2013132.","edition":"2"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1099\/vir.0.2008\/004606-0","article-title":"The multifunctional NS1 protein of influenza A viruses","volume":"89","author":"Hale B. G.","year":"2008","unstructured":"B. G. Hale, R. E. Randall, J. Ort\u00edn, D. Jackson, The multifunctional NS1 protein of influenza A viruses. J. Gen. Virol. 89, 2359\u20132376 (2008).","journal-title":"J. Gen. Virol."},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.tim.2017.12.006","article-title":"Immunomodulatory nonstructural proteins of influenza A viruses","volume":"26","author":"Klemm C.","year":"2018","unstructured":"C. Klemm, Y. Boergeling, S. Ludwig, C. Ehrhardt, Immunomodulatory nonstructural proteins of influenza A viruses. Trends Microbiol. 26, 624\u2013636 (2018).","journal-title":"Trends Microbiol."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"5719","DOI":"10.1074\/jbc.M707195200","article-title":"Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk\/CrkL Src homology 3 domains to activate host cell signaling","volume":"283","author":"Heikkinen L. S.","year":"2008","unstructured":"L. S. Heikkinen ., Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk\/CrkL Src homology 3 domains to activate host cell signaling. J. Biol. Chem. 283, 5719\u20135727 (2008).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.antiviral.2013.06.005","article-title":"The influenza virus NS1 protein as a therapeutic target","volume":"99","author":"Engel D. A.","year":"2013","unstructured":"D. A. Engel, The influenza virus NS1 protein as a therapeutic target. Antiviral Res. 99, 409\u2013416 (2013).","journal-title":"Antiviral Res."},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"14659","DOI":"10.1074\/jbc.RA118.004012","article-title":"Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds","volume":"293","author":"Kleinpeter A. B.","year":"2018","unstructured":"A. B. Kleinpeter, A. S. Jureka, S. M. Falahat, T. J. Green, C. M. Petit, Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds. J. Biol. Chem. 293, 14659\u201314668 (2018).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1128\/JVI.01805-08","article-title":"Novel influenza virus NS1 antagonists block replication and restore innate immune function","volume":"83","author":"Basu D.","year":"2009","unstructured":"D. Basu ., Novel influenza virus NS1 antagonists block replication and restore innate immune function. J. Virol. 83, 1881\u20131891 (2009).","journal-title":"J. Virol."},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.coviro.2015.01.007","article-title":"Functions of the influenza A virus NS1 protein in antiviral defense","volume":"12","author":"Krug R. M.","year":"2015","unstructured":"R. M. Krug, Functions of the influenza A virus NS1 protein in antiviral defense. Curr. Opin. Virol. 12, 1\u20136 (2015).","journal-title":"Curr. Opin. Virol."},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1006\/viro.1998.9508","article-title":"Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems","volume":"252","author":"Garc\u00eda-Sastre A.","year":"1998","unstructured":"A. Garc\u00eda-Sastre ., Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324\u2013330 (1998).","journal-title":"Virology"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"e1003059","DOI":"10.1371\/journal.ppat.1003059","article-title":"Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein","volume":"8","author":"Rajsbaum R.","year":"2012","unstructured":"R. Rajsbaum ., Species-specific inhibition of RIG-I ubiquitination and IFN induction by the influenza A virus NS1 protein. PLoS Pathog. 8, e1003059 (2012).","journal-title":"PLoS Pathog."},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1038\/s41467-018-04214-8","article-title":"Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition","volume":"9","author":"Koliopoulos M. G.","year":"2018","unstructured":"M. G. Koliopoulos ., Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition. Nat. Commun. 9, 1820 (2018).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1128\/JVI.02082-06","article-title":"Influenza A virus NS1 protein activates the PI3K\/Akt pathway to mediate antiapoptotic signaling responses","volume":"81","author":"Ehrhardt C.","year":"2007","unstructured":"C. Ehrhardt ., Influenza A virus NS1 protein activates the PI3K\/Akt pathway to mediate antiapoptotic signaling responses. J. Virol. 81, 3058\u20133067 (2007).","journal-title":"J. Virol."},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"14751","DOI":"10.1038\/ncomms14751","article-title":"An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells","volume":"8","author":"Huang X.","year":"2017","unstructured":"X. Huang ., An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells. Nat. Commun. 8, 14751 (2017).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/nsb1197-896","article-title":"Crystal structure of the unique RNA-binding domain of the influenza virus NS1 protein","volume":"4","author":"Liu J.","year":"1997","unstructured":"J. Liu ., Crystal structure of the unique RNA-binding domain of the influenza virus NS1 protein. Nat. Struct. Biol. 4, 896\u2013899 (1997).","journal-title":"Nat. Struct. Biol."},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/nature07444","article-title":"X-ray structure of NS1 from a highly pathogenic H5N1 influenza virus","volume":"456","author":"Bornholdt Z. A.","year":"2008","unstructured":"Z. A. Bornholdt, B. V. Prasad, X-ray structure of NS1 from a highly pathogenic H5N1 influenza virus. Nature 456, 985\u2013988 (2008).","journal-title":"Nature"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"7100","DOI":"10.1073\/pnas.0602184103","article-title":"The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2\u2032-5\u2032 oligo (A) synthetase\/RNase L pathway","volume":"103","author":"Min J. Y.","year":"2006","unstructured":"J. Y. Min, R. M. Krug, The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2\u2032-5\u2032 oligo (A) synthetase\/RNase L pathway. Proc. Natl. Acad. Sci. U.S.A. 103, 7100\u20137105 (2006).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"20584","DOI":"10.1074\/jbc.M611619200","article-title":"Conserved surface features form the double-stranded RNA binding site of non-structural protein 1 (NS1) from influenza A and B viruses","volume":"282","author":"Yin C.","year":"2007","unstructured":"C. Yin ., Conserved surface features form the double-stranded RNA binding site of non-structural protein 1 (NS1) from influenza A and B viruses. J. Biol. Chem. 282, 20584\u201320592 (2007).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1111\/j.1462-5822.2006.00713.x","article-title":"Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence","volume":"8","author":"Ehrhardt C.","year":"2006","unstructured":"C. Ehrhardt ., Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell. Microbiol. 8, 1336\u20131348 (2006).","journal-title":"Cell. Microbiol."},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1073\/pnas.0910715107","article-title":"Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein","volume":"107","author":"Hale B. G.","year":"2010","unstructured":"B. G. Hale ., Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein. Proc. Natl. Acad. Sci. U.S.A. 107, 1954\u20131959 (2010).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"13093","DOI":"10.1073\/pnas.0805213105","article-title":"Structural basis for suppression of a host antiviral response by influenza A virus","volume":"105","author":"Das K.","year":"2008","unstructured":"K. Das ., Structural basis for suppression of a host antiviral response by influenza A virus. Proc. Natl. Acad. Sci. U.S.A. 105, 13093\u201313098 (2008).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1021\/acschembio.7b00168","article-title":"The molecular mechanisms underlying the hijack of host proteins by the 1918 Spanish influenza virus","volume":"12","author":"Shen Q.","year":"2017","unstructured":"Q. Shen ., The molecular mechanisms underlying the hijack of host proteins by the 1918 Spanish influenza virus. ACS Chem. Biol. 12, 1199\u20131203 (2017).","journal-title":"ACS Chem. Biol."},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1126\/science.1121586","article-title":"Large-scale sequence analysis of avian influenza isolates","volume":"311","author":"Obenauer J. C.","year":"2006","unstructured":"J. C. Obenauer ., Large-scale sequence analysis of avian influenza isolates. Science 311, 1576\u20131580 (2006).","journal-title":"Science"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"14194","DOI":"10.1073\/pnas.0606109103","article-title":"Influenza A virus NS1 protein binds p85beta and activates phosphatidylinositol-3-kinase signaling","volume":"103","author":"Hale B. G.","year":"2006","unstructured":"B. G. Hale, D. Jackson, Y. H. Chen, R. A. Lamb, R. E. Randall, Influenza A virus NS1 protein binds p85beta and activates phosphatidylinositol-3-kinase signaling. Proc. Natl. Acad. Sci. U.S.A. 103, 14194\u201314199 (2006).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.virol.2015.06.009","article-title":"Reorganization of the host cell Crk(L)-PI3 kinase signaling complex by the influenza A virus NS1 protein","volume":"484","author":"Yl\u00f6sm\u00e4ki L.","year":"2015","unstructured":"L. Yl\u00f6sm\u00e4ki, C. Schmotz, E. Yl\u00f6sm\u00e4ki, K. Saksela, Reorganization of the host cell Crk(L)-PI3 kinase signaling complex by the influenza A virus NS1 protein. Virology 484, 146\u2013152 (2015).","journal-title":"Virology"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrd2926","article-title":"Targeting the phosphoinositide 3-kinase pathway in cancer","volume":"8","author":"Liu P.","year":"2009","unstructured":"P. Liu, H. Cheng, T. M. Roberts, J. J. Zhao, Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8, 627\u2013644 (2009).","journal-title":"Nat. Rev. Drug Discov."},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1113\/jphysiol.2009.171223","article-title":"Cation currents in human airway epithelial cells induced by infection with influenza A virus","volume":"587","author":"Gallacher M.","year":"2009","unstructured":"M. Gallacher ., Cation currents in human airway epithelial cells induced by infection with influenza A virus. J. Physiol. 587, 3159\u20133173 (2009).","journal-title":"J. Physiol."},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"5366","DOI":"10.1128\/JVI.06722-11","article-title":"Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence","volume":"86","author":"Ayllon J.","year":"2012","unstructured":"J. Ayllon, B. G. Hale, A. Garc\u00eda-Sastre, Strain-specific contribution of NS1-activated phosphoinositide 3-kinase signaling to influenza A virus replication and virulence. J. Virol. 86, 5366\u20135370 (2012).","journal-title":"J. Virol."},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.4161\/viru.20932","article-title":"Influenza A viruses and PI3K: Are there time, place and manner restrictions?","volume":"3","author":"Ayllon J.","year":"2012","unstructured":"J. Ayllon, A. Garc\u00eda-Sastre, B. G. Hale, Influenza A viruses and PI3K: Are there time, place and manner restrictions? Virulence 3, 411\u2013414 (2012).","journal-title":"Virulence"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1016\/j.str.2015.08.007","article-title":"Structural basis for a novel interaction between the NS1 protein derived from the 1918 influenza virus and RIG-I","volume":"23","author":"Jureka A. S.","year":"2015","unstructured":"A. S. Jureka, A. B. Kleinpeter, G. Cornilescu, C. C. Cornilescu, C. M. Petit, Structural basis for a novel interaction between the NS1 protein derived from the 1918 influenza virus and RIG-I. Structure 23, 2001\u20132010 (2015).","journal-title":"Structure"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"e00721-17","DOI":"10.1128\/JVI.00721-17","article-title":"Functional evolution of influenza virus NS1 protein in currently circulating human 2009 pandemic H1N1 viruses","volume":"91","author":"Clark A. M.","year":"2017","unstructured":"A. M. Clark, A. Nogales, L. Martinez-Sobrido, D. J. Topham, M. L. DeDiego, Functional evolution of influenza virus NS1 protein in currently circulating human 2009 pandemic H1N1 viruses. J. Virol. 91, e00721-17 (2017).","journal-title":"J. Virol."},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"7239","DOI":"10.1074\/jbc.M110.203489","article-title":"Differential effects of NS1 proteins of human pandemic H1N1\/2009, avian highly pathogenic H5N1, and low pathogenic H5N2 influenza A viruses on cellular pre-mRNA polyadenylation and mRNA translation","volume":"286","author":"Kainov D. E.","year":"2011","unstructured":"D. E. Kainov ., Differential effects of NS1 proteins of human pandemic H1N1\/2009, avian highly pathogenic H5N1, and low pathogenic H5N2 influenza A viruses on cellular pre-mRNA polyadenylation and mRNA translation. J. Biol. Chem. 286, 7239\u20137247 (2011).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"13095","DOI":"10.1128\/JVI.02237-12","article-title":"Contribution of NS1 effector domain dimerization to influenza A virus replication and virulence","volume":"86","author":"Ayllon J.","year":"2012","unstructured":"J. Ayllon, R. J. Russell, A. Garc\u00eda-Sastre, B. G. Hale, Contribution of NS1 effector domain dimerization to influenza A virus replication and virulence. J. Virol. 86, 13095\u201313098 (2012).","journal-title":"J. Virol."},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"26050","DOI":"10.1074\/jbc.M111.248765","article-title":"Dimer interface of the effector domain of non-structural protein 1 from influenza A virus: An interface with multiple functions","volume":"286","author":"Aramini J. M.","year":"2011","unstructured":"J. M. Aramini ., Dimer interface of the effector domain of non-structural protein 1 from influenza A virus: An interface with multiple functions. J. Biol. Chem. 286, 26050\u201326060 (2011).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"e17946","DOI":"10.1371\/journal.pone.0017946","article-title":"A transient homotypic interaction model for the influenza A virus NS1 protein effector domain","volume":"6","author":"Kerry P. S.","year":"2011","unstructured":"P. S. Kerry ., A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. PLoS One 6, e17946 (2011).","journal-title":"PLoS One"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"4113","DOI":"10.1128\/JVI.03692-13","article-title":"The influenza A virus protein NS1 displays structural polymorphism","volume":"88","author":"Carrillo B.","year":"2014","unstructured":"B. Carrillo ., The influenza A virus protein NS1 displays structural polymorphism. J. Virol. 88, 4113\u20134122 (2014).","journal-title":"J. Virol."},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.bbrc.2019.08.027","article-title":"The structure and conformational plasticity of the nonstructural protein 1 of the 1918 influenza A virus","volume":"518","author":"Shen Q.","year":"2019","unstructured":"Q. Shen, J. H. Cho, The structure and conformational plasticity of the nonstructural protein 1 of the 1918 influenza A virus. Biochem. Biophys. Res. Commun. 518, 178\u2013182 (2019).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1016\/j.bpj.2016.05.008","article-title":"Binding mechanism of the N-terminal SH3 domain of CrkII and proline-rich motifs in cAbl","volume":"110","author":"Bhatt V. S.","year":"2016","unstructured":"V. S. Bhatt, D. Zeng, I. Krieger, J. C. Sacchettini, J. H. Cho, Binding mechanism of the N-terminal SH3 domain of CrkII and proline-rich motifs in cAbl. Biophys. J. 110, 2630\u20132641 (2016).","journal-title":"Biophys. J."},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1081\/RRS-120037896","article-title":"Thermodynamics of protein-ligand interactions: History, presence, and future aspects","volume":"24","author":"Perozzo R.","year":"2004","unstructured":"R. Perozzo, G. Folkers, L. Scapozza, Thermodynamics of protein-ligand interactions: History, presence, and future aspects. J. Recept. Signal Transduct. Res. 24, 1\u201352 (2004).","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"14116","DOI":"10.1073\/pnas.202485799","article-title":"A simple physical model for binding energy hot spots in protein-protein complexes","volume":"99","author":"Kortemme T.","year":"2002","unstructured":"T. Kortemme, D. Baker, A simple physical model for binding energy hot spots in protein-protein complexes. Proc. Natl. Acad. Sci. U.S.A. 99, 14116\u201314121 (2002).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1038\/s41564-019-0482-x","article-title":"Structural basis for influenza virus NS1 protein block of mRNA nuclear export","volume":"4","author":"Zhang K.","year":"2019","unstructured":"K. Zhang ., Structural basis for influenza virus NS1 protein block of mRNA nuclear export. Nat. Microbiol. 4, 1671\u20131679 (2019).","journal-title":"Nat. Microbiol."},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.tibs.2010.10.002","article-title":"How viruses hijack cell regulation","volume":"36","author":"Davey N. E.","year":"2011","unstructured":"N. E. Davey, G. Trav\u00e9, T. J. Gibson, How viruses hijack cell regulation. Trends Biochem. Sci. 36, 159\u2013169 (2011).","journal-title":"Trends Biochem. Sci."},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1021\/ja017461k","article-title":"An effective method for the discrimination of motional anisotropy and chemical exchange","volume":"124","author":"Kneller J. M.","year":"2002","unstructured":"J. M. Kneller, M. Lu, C. Bracken, An effective method for the discrimination of motional anisotropy and chemical exchange. J. Am. Chem. Soc. 124, 1852\u20131853 (2002).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1021\/ja983961a","article-title":"A relaxation-compensated Carr-Purcell-Meiboom-Gill sequence for characterizing chemical exchange by NMR spectroscopy","volume":"121","author":"Loria J. P.","year":"1999","unstructured":"J. P. Loria, M. Rance, A. G. Palmer, A relaxation-compensated Carr-Purcell-Meiboom-Gill sequence for characterizing chemical exchange by NMR spectroscopy. J. Am. Chem. Soc. 121, 2331\u20132332 (1999).","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1103\/PhysRev.94.630","article-title":"Effects of diffusion on free precession in nuclear magnetic resonance experiments","volume":"94","author":"Carr H. Y.","year":"1954","unstructured":"H. Y. Carr, E. M. Purcell, Effects of diffusion on free precession in nuclear magnetic resonance experiments. Phys. Rev. 94, 630\u2013638 (1954).","journal-title":"Phys. Rev."},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1063\/1.1716296","article-title":"Modified spin-echo method for measuring nuclear relaxation times","volume":"29","author":"Meiboom S.","year":"1958","unstructured":"S. Meiboom, D. Gill, Modified spin-echo method for measuring nuclear relaxation times. Rev. Sci. Instrum. 29, 688\u2013691 (1958).","journal-title":"Rev. Sci. Instrum."},{"key":"e_1_3_4_50_2","first-page":"89","article-title":"A general state-site solution for the chemical exchange produced dependence of T2 upon the Carr-Purcell pulse separation","volume":"6","author":"Carver J. P.","year":"1972","unstructured":"J. P. Carver, R. E. Richards, A general state-site solution for the chemical exchange produced dependence of T2 upon the Carr-Purcell pulse separation. J. Magn. Reson. 6, 89\u2013105 (1972).","journal-title":"J. Magn. Reson."},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10858-011-9478-4","article-title":"SHIFTX2: Significantly improved protein chemical shift prediction","volume":"50","author":"Han B.","year":"2011","unstructured":"B. Han, Y. Liu, S. W. Ginzinger, D. S. Wishart, SHIFTX2: Significantly improved protein chemical shift prediction. J. Biomol. NMR 50, 43\u201357 (2011).","journal-title":"J. Biomol. NMR"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","first-page":"5808","DOI":"10.1074\/jbc.RA118.002353","article-title":"Induction of autophagy by PI3K\/MTOR and PI3K\/MTOR\/BRD4 inhibitors suppresses HIV-1 replication","volume":"293","author":"Campbell G. R.","year":"2018","unstructured":"G. R. Campbell ., Induction of autophagy by PI3K\/MTOR and PI3K\/MTOR\/BRD4 inhibitors suppresses HIV-1 replication. J. Biol. Chem. 293, 5808\u20135820 (2018).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.3390\/v5123192","article-title":"Make yourself at home: Viral hijacking of the PI3K\/Akt signaling pathway","volume":"5","author":"Diehl N.","year":"2013","unstructured":"N. Diehl, H. Schaal, Make yourself at home: Viral hijacking of the PI3K\/Akt signaling pathway. Viruses 5, 3192\u20133212 (2013).","journal-title":"Viruses"},{"key":"e_1_3_4_54_2","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1111\/j.1462-5822.2011.01680.x","article-title":"Phosphatidylinositol-3-kinase (PI3K) is activated by influenza virus vRNA via the pathogen pattern receptor Rig-I to promote efficient type I interferon production","volume":"13","author":"Hrincius E. R.","year":"2011","unstructured":"E. R. Hrincius ., Phosphatidylinositol-3-kinase (PI3K) is activated by influenza virus vRNA via the pathogen pattern receptor Rig-I to promote efficient type I interferon production. Cell. Microbiol. 13, 1907\u20131919 (2011).","journal-title":"Cell. Microbiol."},{"key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/imm.12373","article-title":"Phosphatidylinositol-3-kinase and Akt are required for RIG-I-mediated anti-viral signalling through cross-talk with IPS-1","volume":"144","author":"Yeon S. H.","year":"2015","unstructured":"S. H. Yeon, M. J. Song, H. R. Kang, J. Y. Lee, Phosphatidylinositol-3-kinase and Akt are required for RIG-I-mediated anti-viral signalling through cross-talk with IPS-1. Immunology 144, 312\u2013320 (2015).","journal-title":"Immunology"},{"key":"e_1_3_4_56_2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.virol.2005.11.024","article-title":"Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway","volume":"347","author":"Hayman A.","year":"2006","unstructured":"A. Hayman ., Variation in the ability of human influenza A viruses to induce and inhibit the IFN-beta pathway. Virology 347, 52\u201364 (2006).","journal-title":"Virology"},{"key":"e_1_3_4_57_2","doi-asserted-by":"crossref","first-page":"e01081-17","DOI":"10.1128\/JVI.01081-17","article-title":"Structure-guided functional annotation of the influenza A virus NS1 protein reveals dynamic evolution of the p85\u03b2-binding site during circulation in humans","volume":"91","author":"Lopes A. M.","year":"2017","unstructured":"A. M. Lopes, P. Domingues, R. Zell, B. G. Hale, Structure-guided functional annotation of the influenza A virus NS1 protein reveals dynamic evolution of the p85\u03b2-binding site during circulation in humans. J. Virol. 91, e01081-17 (2017).","journal-title":"J. Virol."},{"key":"e_1_3_4_58_2","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1107\/S0907444994003112","article-title":"The CCP4 suite: Programs for protein crystallography","volume":"50","author":"Collaborative Computational Project, Number 4","year":"1994","unstructured":"Collaborative Computational Project, Number 4, The CCP4 suite: Programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760\u2013763 (1994).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"e_1_3_4_59_2","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: A comprehensive python-based system for macromolecular structure solution","volume":"66","author":"Adams P. D.","year":"2010","unstructured":"P. D. Adams ., PHENIX: A comprehensive python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213\u2013221 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"e_1_3_4_60_2","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley P.","year":"2010","unstructured":"P. Emsley, B. Lohkamp, W. G. Scott, K. Cowtan, Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486\u2013501 (2010).","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","first-page":"030049","DOI":"10.1063\/1.4952872","article-title":"The life science x-ray scattering beamline at NSLS-II","volume":"1741","author":"DiFabio J.","year":"2016","unstructured":"J. DiFabio ., The life science x-ray scattering beamline at NSLS-II. AIP Conf. Proc. 1741, 030049 (2016).","journal-title":"AIP Conf. Proc."},{"key":"e_1_3_4_62_2","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1107\/S0909049512048984","article-title":"Using an in-vacuum CCD detector for simultaneous small- and wide-angle scattering at beamline X9","volume":"20","author":"Yang L.","year":"2013","unstructured":"L. Yang, Using an in-vacuum CCD detector for simultaneous small- and wide-angle scattering at beamline X9. J. Synchrotron Radiat. 20, 211\u2013218 (2013).","journal-title":"J. Synchrotron Radiat."},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","first-page":"W424","DOI":"10.1093\/nar\/gkw389","article-title":"FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles","volume":"44","author":"Schneidman-Duhovny D.","year":"2016","unstructured":"D. Schneidman-Duhovny, M. Hammel, J. A. Tainer, A. Sali, FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles. Nucleic Acids Res. 44, W424\u2013W429 (2016).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_64_2","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: The biomolecular simulation program","volume":"30","author":"Brooks B. R.","year":"2009","unstructured":"B. R. Brooks ., CHARMM: The biomolecular simulation program. J. Comput. Chem. 30, 1545\u20131614 (2009).","journal-title":"J. Comput. Chem."},{"key":"e_1_3_4_65_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1021\/ct200723y","article-title":"Optimization of the CHARMM additive force field for DNA: Improved treatment of the BI\/BII conformational equilibrium","volume":"8","author":"Hart K.","year":"2012","unstructured":"K. Hart ., Optimization of the CHARMM additive force field for DNA: Improved treatment of the BI\/BII conformational equilibrium. J. Chem. Theory Comput. 8, 348\u2013362 (2012).","journal-title":"J. Chem. Theory Comput."},{"key":"e_1_3_4_66_2","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1002\/jcc.23501","article-title":"New faster CHARMM molecular dynamics engine","volume":"35","author":"Hynninen A. P.","year":"2014","unstructured":"A. P. Hynninen, M. F. Crowley, New faster CHARMM molecular dynamics engine. J. Comput. Chem. 35, 406\u2013413 (2014).","journal-title":"J. Comput. Chem."},{"key":"e_1_3_4_67_2","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1101\/gr.849004","article-title":"WebLogo: A sequence logo generator","volume":"14","author":"Crooks G. E.","year":"2004","unstructured":"G. E. Crooks, G. Hon, J. M. Chandonia, S. E. Brenner, WebLogo: A sequence logo generator. Genome Res. 14, 1188\u20131190 (2004).","journal-title":"Genome Res."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1920582117","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1920582117","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T16:51:45Z","timestamp":1654620705000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1920582117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,9]]},"references-count":67,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2020,3,24]]}},"alternative-id":["10.1073\/pnas.1920582117"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1920582117","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,9]]},"assertion":[{"value":"2020-03-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}