title: Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design.
abstract: Zika virus has attracted increasing attention because of its potential for causing human neural disorders, including microcephaly in infants and Guillain-Barré syndrome. Its NS3 helicase domain plays critical roles in NTP-dependent RNA unwinding and translocation during viral replication. Our structural analysis revealed a pre-activation state of NS3 helicase in complex with GTPγS, in which the triphosphate adopts a compact conformation in the absence of any divalent metal ions. In contrast, in the presence of a divalent cation, GTPγS adopts an extended conformation, and the Walker A motif undergoes substantial conformational changes. Both features contribute to more extensive interactions between the GTPγS and the enzyme. Thus, this study provides structural evidence on the allosteric modulation of MgNTP2-on the NS3 helicase activity. Furthermore, the compact conformation of inhibitory NTP identified in this study provides precise information for the rational drug design of small molecule inhibitors for the treatment of ZIKV infection.
authors.affiliation: Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China lyj106@mail.ustc.edu.cn.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors.forename: Yuelong
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, Anhui 230027, China jint@ustc.edu.cn.
authors.forename: Tengchuan
authors.identifier: http://orcid.org/0000-0002-1395-188X
authors.initials: T
authors.lastname: Jin
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020365:RNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000071244:Zika Virus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D000071243:Zika Virus Infection / Q000188:drug therapy / Q000821:virology; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D008670:Metals; D020365:RNA Helicases; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases