دورية أكاديمية
Structural Insights into the Inhibition of Zika Virus NS2B-NS3 Protease by a Small-Molecule Inhibitor.
| العنوان: | Structural Insights into the Inhibition of Zika Virus NS2B-NS3 Protease by a Small-Molecule Inhibitor. |
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| المؤلفون: | Li Y; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Zhang Z; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, Singapore 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, Singapore 636921, Singapore., Phoo WW; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, Singapore 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, Singapore 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 636921, Singapore., Loh YR; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Li R; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Yang HY; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Jansson AE; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Hill J; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Keller TH; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore., Nacro K; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, Singapore 636921, Singapore. Electronic address: knacro@etc.a-star.edu.sg., Luo D; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, Singapore 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, Singapore 636921, Singapore. Electronic address: luodahai@ntu.edu.sg., Kang C; Experimental Therapeutics Centre, Agency for Science, Technology and Research (A(∗)STAR), 31 Biopolis way, Nanos, #03-01, Singapore 138669, Singapore. Electronic address: cbkang@etc.a-star.edu.sg. |
| المصدر: | Structure (London, England : 1993) [Structure] 2018 Apr 03; Vol. 26 (4), pp. 555-564.e3. Date of Electronic Publication: 2018 Mar 08. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101087697 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-4186 (Electronic) Linking ISSN: 09692126 NLM ISO Abbreviation: Structure Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : Cambridge, Mass. : Cell Press Original Publication: London : Current Biology, c1993- |
| مواضيع طبية MeSH: | Antiviral Agents/*chemistry , Protease Inhibitors/*chemistry , Small Molecule Libraries/*chemistry , Viral Nonstructural Proteins/*chemistry , Zika Virus/*chemistry, Amino Acid Sequence ; Antiviral Agents/metabolism ; Binding Sites ; Cloning, Molecular ; Crystallography, X-Ray ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Gene Expression ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Kinetics ; Models, Molecular ; Protease Inhibitors/metabolism ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; RNA Helicases/antagonists & inhibitors ; RNA Helicases/chemistry ; RNA Helicases/genetics ; RNA Helicases/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Serine/chemistry ; Serine/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; Small Molecule Libraries/metabolism ; Substrate Specificity ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Zika Virus/enzymology ; Zika Virus/genetics |
| مستخلص: | Zika virus (ZIKV) infection has become a global public health concern. The viral NS2B-NS3 protease is an attractive antiviral target because of its role in maturation of viral non-structural proteins. Substrate-derived protease inhibitors have been investigated, but it remains challenging to develop them into drugs. Small-molecule inhibitors are of great interest in antiviral drug development. Here we report the structure and dynamics of ZIKV NS2B-NS3 protease covalently bound to a small-molecule inhibitor. Our crystallographic and NMR studies demonstrate that the inhibitor further stabilizes the closed conformation of ZIKV protease. Upon hydrolysis in situ into two fragments, the benzoyl group of the inhibitor forms a covalent bond with the side chain of catalytic residue S135, whereas the second fragment exhibits no obvious molecular interactions with the protease. This study provides a detailed mechanism of action for a covalent inhibitor, which will guide further development of ZIKV protease inhibitors. (Copyright © 2018 Elsevier Ltd. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Zika virus; drug discovery; protease; protease inhibitor; protein dynamics; structure |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (NS2B protein, flavivirus) 0 (NS3 protein, flavivirus) 0 (Protease Inhibitors) 0 (Recombinant Proteins) 0 (Small Molecule Libraries) 0 (Viral Nonstructural Proteins) 452VLY9402 (Serine) EC 3.4.21.- (Serine Endopeptidases) EC 3.6.4.13 (RNA Helicases) |
| تواريخ الأحداث: | Date Created: 20180313 Date Completed: 20190111 Latest Revision: 20190111 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.str.2018.02.005 |
| PMID: | 29526431 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1878-4186 |
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| DOI: | 10.1016/j.str.2018.02.005 |