title: Structural basis of Zika virus helicase in recognizing its substrates.
abstract: The recent explosive outbreak of Zika virus (ZIKV) infection has been reported in South and Central America and the Caribbean. Neonatal microcephaly associated with ZIKV infection has already caused a public health emergency of international concern. No specific vaccines or drugs are currently available to treat ZIKV infection. The ZIKV helicase, which plays a pivotal role in viral RNA replication, is an attractive target for therapy. We determined the crystal structures of ZIKV helicase-ATP-Mn(2+) and ZIKV helicase-RNA. This is the first structure of any flavivirus helicase bound to ATP. Comparisons with related flavivirus helicases have shown that although the critical P-loop in the active site has variable conformations among different species, it adopts an identical mode to recognize ATP/Mn(2+). The structure of ZIKV helicase-RNA has revealed that upon RNA binding, rotations of the motor domains can cause significant conformational changes. Strikingly, although ZIKV and dengue virus (DENV) apo-helicases share conserved residues for RNA binding, their different manners of motor domain rotations result in distinct individual modes for RNA recognition. It suggests that flavivirus helicases could have evolved a conserved engine to convert chemical energy from nucleoside triphosphate to mechanical energy for RNA unwinding, but different motor domain rotations result in variable RNA recognition modes to adapt to individual viral replication.
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.|Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin, 300457, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Tian
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Ji
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Zuokun
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, 44195, USA.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Chi
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Mu
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China.
authors.forename: Zefang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Lou
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin, 300072, China. yanght@tju.edu.cn.|Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin, 300457, China. yanght@tju.edu.cn.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
mesh_terms: D018360:Crystallography, X-Ray; D000072417:Protein Domains; D020365:RNA Helicases / Q000737:chemistry*; D012367:RNA, Viral / Q000737:chemistry*; D014764:Viral Proteins / Q000737:chemistry*; D000071244:Zika Virus / Q000201:enzymology*
chemical_list: D012367:RNA, Viral; D014764:Viral Proteins; D020365:RNA Helicases
keywords: ATP; Zika virus; crystal structure; flavivirus; helicase