{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T06:16:23Z","timestamp":1762668983029,"version":"build-2065373602"},"reference-count":40,"publisher":"Elsevier BV","issue":"3","license":[{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2017,2,19]],"date-time":"2017-02-19T00:00:00Z","timestamp":1487462400000},"content-version":"am","delay-in-days":384,"URL":"http:\/\/www.elsevier.com\/open-access\/userlicense\/1.0\/"}],"funder":[{"name":"Mallinckrodt Foundation Faculty Scholar Award"},{"name":"Smith Family Foundation Excellence in Biomedical Research Award"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1DP2GM119162","1R03AR067503"],"award-info":[{"award-number":["1DP2GM119162","1R03AR067503"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation Graduate Research Fellowship","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Molecular Biology"],"published-print":{"date-parts":[[2016,2]]},"DOI":"10.1016\/j.jmb.2015.12.019","type":"journal-article","created":{"date-parts":[[2015,12,31]],"date-time":"2015-12-31T11:46:52Z","timestamp":1451562412000},"page":"533-537","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Path of Least Resistance: Mechanisms to Reduce Influenza's Sensitivity to Oseltamivir"],"prefix":"10.1016","volume":"428","author":[{"given":"Angela M.","family":"Phillips","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Shoulders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.jmb.2015.12.019_bb0005","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrmicro1208","article-title":"Influenza: Lessons from past pandemics, warnings from current incidents","volume":"3","author":"Horimoto","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0010","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3851\/IMP2067","article-title":"Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods","volume":"17","author":"Nguyen","year":"2012","journal-title":"Antivir. Ther."},{"key":"10.1016\/j.jmb.2015.12.019_bb0015","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0140-6736(04)16934-1","article-title":"Resistant influenza A viruses in children treated with oseltamivir: Descriptive study","volume":"364","author":"Kiso","year":"2004","journal-title":"Lancet"},{"key":"10.1016\/j.jmb.2015.12.019_bb0020","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1086\/518936","article-title":"Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide","volume":"196","author":"Deyde","year":"2007","journal-title":"J. Infect. Dis."},{"key":"10.1016\/j.jmb.2015.12.019_bb0025","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1056\/NEJMp0900648","article-title":"Global transmission of oseltamivir-resistant influenza","volume":"360","author":"Moscona","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.jmb.2015.12.019_bb0030","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1002\/j.1460-2075.1985.tb04038.x","article-title":"The molecular basis of the specific anti-influenza action of amantadine","volume":"4","author":"Hay","year":"1985","journal-title":"EMBO J."},{"key":"10.1016\/j.jmb.2015.12.019_bb0035","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/prot.340060402","article-title":"The neuraminidase of influenza virus","volume":"6","author":"Air","year":"1989","journal-title":"Proteins"},{"key":"10.1016\/j.jmb.2015.12.019_bb0040","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/rmv.352","article-title":"Functional balance between haemagglutinin and neuraminidase in influenza virus infections","volume":"12","author":"Wagner","year":"2002","journal-title":"Rev. Med. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0045","doi-asserted-by":"crossref","first-page":"5351","DOI":"10.1021\/bi00391a020","article-title":"Site-directed mutation of the active site of influenza neuraminidase and implications for the catalytic mechanism","volume":"26","author":"Lentz","year":"1987","journal-title":"Biochemistry"},{"key":"10.1016\/j.jmb.2015.12.019_bb0050","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/prot.340140302","article-title":"The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor","volume":"14","author":"Varghese","year":"1992","journal-title":"Proteins"},{"key":"10.1016\/j.jmb.2015.12.019_bb0055","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/363418a0","article-title":"Rational design of potent sialidase-based inhibitors of influenza virus replication","volume":"363","author":"von Itzstein","year":"1993","journal-title":"Nature"},{"key":"10.1016\/j.jmb.2015.12.019_bb0060","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1021\/ja963036t","article-title":"Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: Design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity","volume":"119","author":"Kim","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"10.1016\/j.jmb.2015.12.019_bb0065","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2174\/0929867003374886","article-title":"Discovery and development of GS 4104 (oseltamivir): An orally active influenza neuraminidase inhibitor","volume":"7","author":"Lew","year":"2000","journal-title":"Curr. Med. Chem."},{"key":"10.1016\/j.jmb.2015.12.019_bb0070","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.1016\/j.vaccine.2009.07.017","article-title":"Structural basis for oseltamivir resistance of influenza viruses","volume":"27","author":"Collins","year":"2009","journal-title":"Vaccine"},{"key":"10.1016\/j.jmb.2015.12.019_bb0075","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1038\/nature06956","article-title":"Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants","volume":"453","author":"Collins","year":"2008","journal-title":"Nature"},{"key":"10.1016\/j.jmb.2015.12.019_bb0080","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1006\/viro.1998.9194","article-title":"The interaction of neuraminidase and hemagglutinin mutations in influenza virus in resistance to 4-guanidino-Neu5Ac2en","volume":"246","author":"Blick","year":"1998","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0085","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0166-3542(02)00053-0","article-title":"The H274Y mutation in the influenza A\/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo","volume":"55","author":"Ives","year":"2002","journal-title":"Antivir. Res."},{"key":"10.1016\/j.jmb.2015.12.019_bb0090","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1126\/science.1187816","article-title":"Permissive secondary mutations enable the evolution of influenza oseltamivir resistance","volume":"328","author":"Bloom","year":"2010","journal-title":"Science"},{"key":"10.1016\/j.jmb.2015.12.019_bb0095","doi-asserted-by":"crossref","first-page":"e1004065","DOI":"10.1371\/journal.ppat.1004065","article-title":"Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses","volume":"10","author":"Butler","year":"2014","journal-title":"PLoS Pathog."},{"key":"10.1016\/j.jmb.2015.12.019_bb0100","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1128\/JVI.01067-13","article-title":"Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro","volume":"88","author":"Renzette","year":"2014","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0105","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1128\/JVI.00047-11","article-title":"Effect of an asparagine-to-serine mutation at position 294 in neuraminidase on the pathogenicity of highly pathogenic H5N1 influenza A virus","volume":"85","author":"Kiso","year":"2011","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0110","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1177\/135965350601100804","article-title":"Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds","volume":"11","author":"Abed","year":"2006","journal-title":"Antivir. Ther."},{"key":"10.1016\/j.jmb.2015.12.019_bb0115","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1128\/AAC.01848-13","article-title":"A conformational restriction in the influenza A virus neuraminidase binding site by R152 results in a combinational effect of I222T and H274Y on oseltamivir resistance","volume":"58","author":"Huang","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.jmb.2015.12.019_bb0120","doi-asserted-by":"crossref","first-page":"5419","DOI":"10.1128\/JVI.03513-14","article-title":"Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses","volume":"89","author":"Marjuki","year":"2015","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0125","doi-asserted-by":"crossref","first-page":"2972","DOI":"10.1128\/jvi.67.6.2972-2980.1993","article-title":"Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase","volume":"67","author":"Colman","year":"1993","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0130","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jmb.2015.11.027","article-title":"A balance between inhibitor binding and substrate processing confers influenza drug resistance","volume":"428","author":"Jiang","year":"2016","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0135","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/nmeth.3027","article-title":"Deep mutational scanning: A new style of protein science","volume":"11","author":"Fowler","year":"2014","journal-title":"Nat. Methods"},{"year":"2014","series-title":"The inherent mutational tolerance and antigenic evolvability of influenza hemagglutinin","author":"Thyagarajan","key":"10.1016\/j.jmb.2015.12.019_bb0140"},{"key":"10.1016\/j.jmb.2015.12.019_bb0145","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1093\/molbev\/msu173","article-title":"An experimentally determined evolutionary model dramatically improves phylogenetic fit","volume":"31","author":"Bloom","year":"2014","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0150","doi-asserted-by":"crossref","first-page":"4942","DOI":"10.1038\/srep04942","article-title":"High-throughput profiling of influenza A virus hemagglutinin gene at single-nucleotide resolution","volume":"4","author":"Wu","year":"2014","journal-title":"Sci. Rep."},{"key":"10.1016\/j.jmb.2015.12.019_bb0155","doi-asserted-by":"crossref","first-page":"10157","DOI":"10.1128\/JVI.01494-14","article-title":"High-throughput identification of loss-of-function mutations for anti-interferon activity in the influenza A virus NS segment","volume":"88","author":"Wu","year":"2014","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0160","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1128\/JVI.01658-12","article-title":"Systematic identification of H274Y compensatory mutations in influenza A virus neuraminidase by high-throughput screening","volume":"87","author":"Wu","year":"2013","journal-title":"J. Virol."},{"key":"10.1016\/j.jmb.2015.12.019_bb0165","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nmeth.1492","article-title":"High-resolution mapping of protein sequence\u2013function relationships","volume":"7","author":"Fowler","year":"2010","journal-title":"Nat. Methods"},{"key":"10.1016\/j.jmb.2015.12.019_bb0170","doi-asserted-by":"crossref","first-page":"20248","DOI":"10.1073\/pnas.1320524110","article-title":"Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins","volume":"110","author":"Heaton","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jmb.2015.12.019_bb0175","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/nature11500","article-title":"The spatial architecture of protein function and adaptation","volume":"491","author":"McLaughlin","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.jmb.2015.12.019_bb0180","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1038\/nprot.2012.069","article-title":"Fitness analyses of all possible point mutations for regions of genes in yeast","volume":"7","author":"Hietpas","year":"2012","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.jmb.2015.12.019_bb0185","doi-asserted-by":"crossref","first-page":"7896","DOI":"10.1073\/pnas.1016024108","article-title":"Experimental illumination of a fitness landscape","volume":"108","author":"Hietpas","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jmb.2015.12.019_bb0190","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1534\/genetics.113.156190","article-title":"A Bayesian MCMC approach to assess the complete distribution of fitness effects of new mutations: Uncovering the potential for adaptive walks in challenging environments","volume":"196","author":"Bank","year":"2014","journal-title":"Genetics"},{"key":"10.1016\/j.jmb.2015.12.019_bb0195","doi-asserted-by":"crossref","first-page":"e1002914","DOI":"10.1371\/journal.ppat.1002914","article-title":"H1N1 2009 pandemic influenza virus: Resistance of the I223R neuraminidase mutant explained by kinetic and structural analysis","volume":"8","author":"van der Vries","year":"2012","journal-title":"PLoS Pathog."},{"key":"10.1016\/j.jmb.2015.12.019_bb0200","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.3390\/v2112509","article-title":"Molecular basis for drug resistance in HIV-1 protease","volume":"2","author":"Ali","year":"2010","journal-title":"Viruses"}],"container-title":["Journal of Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S002228361500710X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S002228361500710X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T06:14:09Z","timestamp":1762668849000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S002228361500710X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2016,2]]}},"alternative-id":["S002228361500710X"],"URL":"https:\/\/doi.org\/10.1016\/j.jmb.2015.12.019","relation":{},"ISSN":["0022-2836"],"issn-type":[{"type":"print","value":"0022-2836"}],"subject":[],"published":{"date-parts":[[2016,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"The Path of Least Resistance: Mechanisms to Reduce Influenza's Sensitivity to Oseltamivir","name":"articletitle","label":"Article Title"},{"value":"Journal of Molecular Biology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jmb.2015.12.019","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"https:\/\/doi.org\/10.1016\/j.jmb.2015.11.027","name":"associatedlink","label":"CrossRef DOI link to the associated document"},{"value":"simple-article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2015 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}]}}