دورية أكاديمية
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Crystal structures of full length DENV4 NS2B-NS3 reveal the dynamic interaction between NS2B and NS3.

التفاصيل البيبلوغرافية
العنوان: Crystal structures of full length DENV4 NS2B-NS3 reveal the dynamic interaction between NS2B and NS3.
المؤلفون: Phoo WW; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 636921, Singapore., El Sahili A; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 636921, Singapore., Zhang Z; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, 636921, Singapore., Chen MW; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, 636921, Singapore., Liew CW; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 636921, Singapore., Lescar J; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 636921, Singapore. Electronic address: julien@ntu.edu.sg., Vasudevan SG; Emerging Infectious Diseases, DUKE NUS Graduate Medical School, 8 College Road, 09, Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute fof Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. Electronic address: subhash.vasudevan@duke-nus.edu.sg., Luo D; Lee Kong Chian School of Medicine, Nanyang Technological University, EMB 03-07, 59 Nanyang Drive, 636921, Singapore; NTU Institute of Structural Biology, Nanyang Technological University, EMB 06-01, 59 Nanyang Drive, 636921, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 636921, Singapore. Electronic address: luodahai@ntu.edu.sg.
المصدر: Antiviral research [Antiviral Res] 2020 Oct; Vol. 182, pp. 104900. Date of Electronic Publication: 2020 Aug 05.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8109699 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9096 (Electronic) Linking ISSN: 01663542 NLM ISO Abbreviation: Antiviral Res Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: [Amsterdam ; New York : Elsevier/North-Holland Biomedical Press, c1981-
مواضيع طبية MeSH: Dengue Virus/*chemistry , Viral Nonstructural Proteins/*chemistry , Viral Nonstructural Proteins/*metabolism, Crystallography, X-Ray ; Dengue Virus/enzymology ; Protein Conformation ; Protein Interaction Domains and Motifs ; RNA Helicases/chemistry ; RNA Helicases/metabolism ; Serine Endopeptidases/chemistry ; Serine Endopeptidases/metabolism ; Virus Replication
مستخلص: Flavivirus is a genus of the Flaviviridae family which includes significant emerging and re-emerging human disease-causing arboviruses such as dengue and Zika viruses. Flaviviral non-structural protein 3 (NS3) protease-helicase plays essential roles in viral replication and is an attractive antiviral target. A construct which connects the cytoplasmic cofactor region of NS2B and NS3 protease with an artificial glycine-rich flexible linker has been widely used for structural, biochemical and drug-screening studies. The effect of this linker on the dynamics and enzymatic activity of the protease has been studied by several biochemical and NMR methods but the findings remained inconclusive. Here, we designed and carried out a comparative study of constructs of NS2B cofactor joined to the full length DENV4 NS3 in three different ways, namely bNS2B 47 NS3 (bivalent), eNS2B 47 NS3(enzymatically cleavable) and gNS2B 47 NS3 (glycine-rich linker). We report the crystal structures of linked and unlinked NS2B 47 -NS3 constructs in their free state and in complex with bovine pancreatic trypsin inhibitor (BPTI). These structures demonstrate that the NS2B cofactor predominantly adopts a closed conformation in complex with full-length NS3. The glycine-rich linker between NS2B and NS3 may promote the open conformation which interferes with protease activity. This negative impact on the enzyme structure and function is restricted to the protease activity as the ATPase activity is not affected in vitro.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Anti viral drug discovery; Biochemistry; Flavivirus NS3; NS2B NS3 protease; X-ray crystallography
المشرفين على المادة: 0 (NS3 protein, flavivirus)
0 (Viral Nonstructural Proteins)
0 (nonstructural protein 2B, Dengue virus)
EC 3.4.21.- (Serine Endopeptidases)
EC 3.6.4.13 (RNA Helicases)
تواريخ الأحداث: Date Created: 20200809 Date Completed: 20210712 Latest Revision: 20210712
رمز التحديث: 20221213
DOI: 10.1016/j.antiviral.2020.104900
PMID: 32763315
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-9096
DOI:10.1016/j.antiviral.2020.104900