Structure of importin-[alpha] bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein

A non-classical nuclear localization signal (ncNLS) of influenza A virus nucleoprotein (NP) is critical for nuclear import of viral genomic RNAs that transcribe and replicate in the nucleus of infected cells. Here we report a 2.3 Å resolution crystal structure of mouse importin-α1 in complex with NP...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2015-10, Vol.5, p.15055
Main Authors: Nakada, Ryohei, Hirano, Hidemi, Matsuura, Yoshiyuki
Format: Article
Language:English
Subjects:
Affinity
Binding sites
Crystal structure
Cytotoxicity
Drug development
Influenza
Influenza A
Localization
Nuclear transport
Structure-function relationships
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page
container_issue
container_start_page 15055
container_title Scientific reports
container_volume 5
creator Nakada, Ryohei
Hirano, Hidemi
Matsuura, Yoshiyuki
description A non-classical nuclear localization signal (ncNLS) of influenza A virus nucleoprotein (NP) is critical for nuclear import of viral genomic RNAs that transcribe and replicate in the nucleus of infected cells. Here we report a 2.3 Å resolution crystal structure of mouse importin-α1 in complex with NP ncNLS. The structure reveals that NP ncNLS binds specifically and exclusively to the minor NLS-binding site of importin-α. Structural and functional analyses identify key binding pockets on importin-α as potential targets for antiviral drug development. Unlike many other NLSs, NP ncNLS binds to the NLS-binding domain of importin-α weakly with micromolar affinity. These results suggest that a modest inhibitor with low affinity to importin-α could have anti-influenza activity with minimal cytotoxicity.
doi_str_mv 10.1038/srep15055
format article
fullrecord <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_journals_1899773226</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1899773226</sourcerecordid><originalsourceid>FETCH-proquest_journals_18997732263</originalsourceid><addsrcrecordid>eNqNTstKBDEQDILgonvwDxo8jyaZjbtzFFG8601kaceM20vsHtOJ4H69Af0A61IU9aCMOXf20tl-c6U5zi7YEI7MwttV6Hzv_YlZqu5tQ_DDyg0L8_1Ych1LzRFkAvqYJRfi7hnTvMMXeJXKb1AEEFi4GxOq0ogJuI4pYoYkTdEBCwmD0js3rw2VXQTiKdXIB4Qb-KJc9bckc5YSic_M8YRJ4_KPT83F_d3T7UPX_M8atWz3UnPb063bDMN63f5f9_9L_QCKI1N0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1899773226</pqid></control><display><type>article</type><title>Structure of importin-[alpha] bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein</title><source>PubMed Central Free</source><source>Publicly Available Content Database</source><source>Free Full-Text Journals in Chemistry</source><source>Springer Nature - nature.com Journals - Fully Open Access</source><creator>Nakada, Ryohei ; Hirano, Hidemi ; Matsuura, Yoshiyuki</creator><creatorcontrib>Nakada, Ryohei ; Hirano, Hidemi ; Matsuura, Yoshiyuki</creatorcontrib><description>A non-classical nuclear localization signal (ncNLS) of influenza A virus nucleoprotein (NP) is critical for nuclear import of viral genomic RNAs that transcribe and replicate in the nucleus of infected cells. Here we report a 2.3 Å resolution crystal structure of mouse importin-α1 in complex with NP ncNLS. The structure reveals that NP ncNLS binds specifically and exclusively to the minor NLS-binding site of importin-α. Structural and functional analyses identify key binding pockets on importin-α as potential targets for antiviral drug development. Unlike many other NLSs, NP ncNLS binds to the NLS-binding domain of importin-α weakly with micromolar affinity. These results suggest that a modest inhibitor with low affinity to importin-α could have anti-influenza activity with minimal cytotoxicity.</description><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep15055</identifier><language>eng</language><publisher>London: Nature Publishing Group</publisher><subject>Affinity ; Binding sites ; Crystal structure ; Cytotoxicity ; Drug development ; Influenza ; Influenza A ; Localization ; Nuclear transport ; Structure-function relationships</subject><ispartof>Scientific reports, 2015-10, Vol.5, p.15055</ispartof><rights>Copyright Nature Publishing Group Oct 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1899773226/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1899773226?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,25753,27924,27925,37012,44590,75126</link.rule.ids></links><search><creatorcontrib>Nakada, Ryohei</creatorcontrib><creatorcontrib>Hirano, Hidemi</creatorcontrib><creatorcontrib>Matsuura, Yoshiyuki</creatorcontrib><title>Structure of importin-[alpha] bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein</title><title>Scientific reports</title><description>A non-classical nuclear localization signal (ncNLS) of influenza A virus nucleoprotein (NP) is critical for nuclear import of viral genomic RNAs that transcribe and replicate in the nucleus of infected cells. Here we report a 2.3 Å resolution crystal structure of mouse importin-α1 in complex with NP ncNLS. The structure reveals that NP ncNLS binds specifically and exclusively to the minor NLS-binding site of importin-α. Structural and functional analyses identify key binding pockets on importin-α as potential targets for antiviral drug development. Unlike many other NLSs, NP ncNLS binds to the NLS-binding domain of importin-α weakly with micromolar affinity. These results suggest that a modest inhibitor with low affinity to importin-α could have anti-influenza activity with minimal cytotoxicity.</description><subject>Affinity</subject><subject>Binding sites</subject><subject>Crystal structure</subject><subject>Cytotoxicity</subject><subject>Drug development</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Localization</subject><subject>Nuclear transport</subject><subject>Structure-function relationships</subject><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNqNTstKBDEQDILgonvwDxo8jyaZjbtzFFG8601kaceM20vsHtOJ4H69Af0A61IU9aCMOXf20tl-c6U5zi7YEI7MwttV6Hzv_YlZqu5tQ_DDyg0L8_1Ych1LzRFkAvqYJRfi7hnTvMMXeJXKb1AEEFi4GxOq0ogJuI4pYoYkTdEBCwmD0js3rw2VXQTiKdXIB4Qb-KJc9bckc5YSic_M8YRJ4_KPT83F_d3T7UPX_M8atWz3UnPb063bDMN63f5f9_9L_QCKI1N0</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Nakada, Ryohei</creator><creator>Hirano, Hidemi</creator><creator>Matsuura, Yoshiyuki</creator><general>Nature Publishing Group</general><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope></search><sort><creationdate>20151001</creationdate><title>Structure of importin-[alpha] bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein</title><author>Nakada, Ryohei ; Hirano, Hidemi ; Matsuura, Yoshiyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_18997732263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Affinity</topic><topic>Binding sites</topic><topic>Crystal structure</topic><topic>Cytotoxicity</topic><topic>Drug development</topic><topic>Influenza</topic><topic>Influenza A</topic><topic>Localization</topic><topic>Nuclear transport</topic><topic>Structure-function relationships</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nakada, Ryohei</creatorcontrib><creatorcontrib>Hirano, Hidemi</creatorcontrib><creatorcontrib>Matsuura, Yoshiyuki</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Health &amp; Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Science Journals</collection><collection>ProQuest Biological Science Journals</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nakada, Ryohei</au><au>Hirano, Hidemi</au><au>Matsuura, Yoshiyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure of importin-[alpha] bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein</atitle><jtitle>Scientific reports</jtitle><date>2015-10-01</date><risdate>2015</risdate><volume>5</volume><spage>15055</spage><pages>15055-</pages><eissn>2045-2322</eissn><abstract>A non-classical nuclear localization signal (ncNLS) of influenza A virus nucleoprotein (NP) is critical for nuclear import of viral genomic RNAs that transcribe and replicate in the nucleus of infected cells. Here we report a 2.3 Å resolution crystal structure of mouse importin-α1 in complex with NP ncNLS. The structure reveals that NP ncNLS binds specifically and exclusively to the minor NLS-binding site of importin-α. Structural and functional analyses identify key binding pockets on importin-α as potential targets for antiviral drug development. Unlike many other NLSs, NP ncNLS binds to the NLS-binding domain of importin-α weakly with micromolar affinity. These results suggest that a modest inhibitor with low affinity to importin-α could have anti-influenza activity with minimal cytotoxicity.</abstract><cop>London</cop><pub>Nature Publishing Group</pub><doi>10.1038/srep15055</doi><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier EISSN: 2045-2322
ispartof Scientific reports, 2015-10, Vol.5, p.15055
issn 2045-2322
language eng
recordid cdi_proquest_journals_1899773226
source PubMed Central Free; Publicly Available Content Database; Free Full-Text Journals in Chemistry; Springer Nature - nature.com Journals - Fully Open Access
subjects Affinity
Binding sites
Crystal structure
Cytotoxicity
Drug development
Influenza
Influenza A
Localization
Nuclear transport
Structure-function relationships
title Structure of importin-[alpha] bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T00%3A09%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structure%20of%20importin-%5Balpha%5D%20bound%20to%20a%20non-classical%20nuclear%20localization%20signal%20of%20the%20influenza%20A%20virus%20nucleoprotein&rft.jtitle=Scientific%20reports&rft.au=Nakada,%20Ryohei&rft.date=2015-10-01&rft.volume=5&rft.spage=15055&rft.pages=15055-&rft.eissn=2045-2322&rft_id=info:doi/10.1038/srep15055&rft_dat=%3Cproquest%3E1899773226%3C/proquest%3E%3Cgrp_id%3Ecdi_FETCH-proquest_journals_18997732263%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1899773226&rft_id=info:pmid/&rfr_iscdi=true