دورية أكاديمية
Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment.
| العنوان: | Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment. |
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| المؤلفون: | Landeras-Bueno S; La Jolla Institute for Immunology, La Jolla, California, USA.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Oda SI; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Norris MJ; La Jolla Institute for Immunology, La Jolla, California, USA.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Li Salie Z; La Jolla Institute for Immunology, La Jolla, California, USA.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Guenaga J; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Wyatt RT; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA., Saphire EO; La Jolla Institute for Immunology, La Jolla, California, USA erica@lji.org.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.; Skaggs Institute for Chemical Biology, La Jolla, California, USA. |
| المصدر: | MBio [mBio] 2019 Jul 23; Vol. 10 (4). Date of Electronic Publication: 2019 Jul 23. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Ebolavirus/*drug effects , Filoviridae/*drug effects , Nucleoproteins/*chemistry , Viral Regulatory and Accessory Proteins/*chemistry, Crystallography, X-Ray ; Filoviridae/pathogenicity ; Phosphoproteins/chemistry ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs |
| مستخلص: | The filoviruses are etiological agents of life-threatening hemorrhagic fever with high mortality rate and risk of potential outbreak. Among members of this family, the Ebola (EBOV), Sudan (SUDV), and Marburg (MARV) viruses are considered the most pathogenic for humans. The ebolavirus nucleoprotein (NP) is the most abundant protein in infected cells and is essential for viral transcription and replication; thus, it represents an attractive target for therapeutic intervention. Here, we present the structure of SUDV NP in complex with the amino-terminal portion of the phosphoprotein VP35 at 2.3 Å. This structure captures VP35 chaperoning SUDV NP in a monomeric and RNA-free state. This transient state has been proposed to be key to maintaining a pool of monomeric and RNA-free NPs prior to NP-NP polymerization and encapsidation of the viral RNA genome. This structure also reveals a newly visualized interaction between NP and VP35, a well-defined beta sheet that is not present in previous structures. Affinity binding assays demonstrate that this beta sheet is essential for maintaining the high-affinity interaction between VP35 and a hydrophobic pocket on SUDV NP, and electron microscopy indicates the importance of this binding interaction to the oligomeric state and assembly of NP in human cells. Complementary structure-directed mutagenesis identifies critical residues conserved across the filovirus family that could be targeted by broadly effective antivirals. IMPORTANCE Outbreaks of the filoviruses can be unpredictable in timing, location, and identity of the causative virus, with each of Ebola virus, Sudan virus, Bundibugyo virus, and Marburg virus reemerging in the last several years to cause human disease with 30 to 90% lethality. The 2014-2016 outbreak in particular, with nearly 30,000 patients, highlighted the ability of these viruses to emerge unexpectedly and spread rapidly. Two ebolavirus outbreaks have emerged this year, yet we still lack FDA-approved drugs with pan-filovirus activity to treat existing and emergent ebolaviruses. For all filoviruses, the interaction between the nucleoprotein and the phosphoprotein is essential for the virus life cycle and is a potential target for therapeutic intervention. In this report, we describe the crystal structure of the SUDV nucleoprotein with the interacting domain of the viral phosphoprotein, and we identify residues critical for high-affinity interaction and for control of the oligomeric state of the nucleoprotein. Structural comparison of this heterodimer with other members of the filovirus family allowed us to find conserved and essential atomic features that will facilitate understanding of the virus life cycle and the rational design of antivirals. (Copyright © 2019 Landeras-Bueno et al.) |
| References: | Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42. (PMID: 21460441) mBio. 2014 Nov 04;5(6):e02011. (PMID: 25370495) J Virol. 2017 Aug 24;91(18):. (PMID: 28659479) Virus Res. 2009 Mar;140(1-2):8-14. (PMID: 19041915) Nat Struct Mol Biol. 2014 Sep;21(9):754-9. (PMID: 25108352) Biochemistry. 2004 Mar 16;43(10):2863-70. (PMID: 15005621) J Virol. 1998 Nov;72(11):8756-64. (PMID: 9765419) Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501. (PMID: 20383002) Future Microbiol. 2013 Dec;8(12):1537-45. (PMID: 24266354) J Virol. 2002 Sep;76(17):8532-9. (PMID: 12163572) Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21. (PMID: 20124702) Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32. (PMID: 20124692) Nat Commun. 2013;4:1591. (PMID: 23481399) Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4275-80. (PMID: 22371572) Virology. 2013 Jul 5;441(2):135-45. (PMID: 23582637) Virol J. 2017 Feb 7;14(1):22. (PMID: 28173821) N Engl J Med. 2015 Feb 5;372(6):584-7. (PMID: 25539446) Curr Top Med Chem. 2017;17(20):2271-2285. (PMID: 28240183) J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254) J Virol. 1995 Feb;69(2):849-55. (PMID: 7815552) J Virol. 2009 Sep;83(17):8993-7. (PMID: 19515768) J Gen Virol. 2002 Apr;83(Pt 4):723-734. (PMID: 11907320) Nature. 2018 Nov;563(7729):137-140. (PMID: 30333622) Nat Biotechnol. 2010 Jun;28(6):600-5. (PMID: 20512121) Cell Rep. 2015 Jul 7;12(1):140-149. (PMID: 26119732) Cell Host Microbe. 2013 Jul 17;14(1):74-84. (PMID: 23870315) Future Virol. 2007 Mar;2(2):205-215. (PMID: 24093048) Nature. 2017 Nov 16;551(7680):394-397. (PMID: 29144446) Virology. 1987 Apr;157(2):414-20. (PMID: 2881398) PLoS Pathog. 2011 Sep;7(9):e1002248. (PMID: 21960769) J Virol. 2009 Apr;83(7):3069-77. (PMID: 19153231) Mol Cell. 2002 Aug;10(2):307-16. (PMID: 12191476) Virus Res. 1993 Sep;29(3):215-40. (PMID: 8237108) Virology. 2015 May;479-480:532-44. (PMID: 25824479) Virology. 2002 May 10;296(2):300-7. (PMID: 12069528) Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15366-71. (PMID: 21896751) J Virol. 2007 Jan;81(1):182-92. (PMID: 17065211) Nat Microbiol. 2018 Oct;3(10):1084-1089. (PMID: 30150734) Proc Natl Acad Sci U S A. 1985 Mar;82(6):1785-9. (PMID: 3872457) Cell Rep. 2015 Apr 21;11(3):376-89. (PMID: 25865894) Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):624-9. (PMID: 17202263) Virology. 2013 Aug 1;442(2):97-100. (PMID: 23711383) |
| معلومات مُعتمدة: | R01 AI118016 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: RNA virus replication; Sudan virus; crystal structure; ebolavirus; nucleoprotein; phosphoprotein |
| المشرفين على المادة: | 0 (Nucleoproteins) 0 (Phosphoproteins) 0 (VP35 protein, filovirus) 0 (Viral Regulatory and Accessory Proteins) |
| تواريخ الأحداث: | Date Created: 20190725 Date Completed: 20200428 Latest Revision: 20201218 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC6650547 |
| DOI: | 10.1128/mBio.00734-19 |
| PMID: | 31337716 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mBio.00734-19 |