title: Structure of the NS5 methyltransferase from Zika virus and implications in inhibitor design.
abstract: Recent outbreak of flavivirus Zika virus (ZIKV) in America has urged the basic as well as translational studies of this important human pathogen. The nonstructural protein 5 (NS5) of the flavivirus has an N-terminal methyltransferase (MTase) domain that plays critical roles in viral RNA genome capping. The null mutant of NS5 MTase is lethal for virus. Therefore, NS5 is a potential drug target for the treatment of Zika virus infection. In this study, we determined crystal structures of the ZIKV MTase in complex with GTP and RNA cap analogue7meGpppA. Structural analyses revealed highly conserved GTP/cap-binding pocket and S-adenosylmethionine (SAM)-binding pocket. Two conformations of the second base of the cap were identified, which suggests the flexibility of RNA conformation. In addition, the ligand-binding pockets identified a continuous region of hotspots suitable for drug design. Docking calculation shows that the Dengue virus inhibitor compound 10 may bind to the ZIKV MTase.
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: Caiying
authors.initials: C
authors.lastname: Zhang
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: Tingting
authors.initials: T
authors.lastname: Feng
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: Jinbo
authors.initials: J
authors.lastname: Cheng
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: 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: Xueying
authors.initials: X
authors.lastname: Yin
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: Weihong
authors.initials: W
authors.lastname: Zeng
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. Electronic address: jint@ustc.edu.cn.
authors.forename: Tengchuan
authors.initials: T
authors.lastname: Jin
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000648:ultrastructure*; D000071244:Zika Virus / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; C096041:NS5 protein, flavivirus; D017361:Viral Nonstructural Proteins
keywords: Antiviral inhibitor design; Flavivirus family virus; Methyltransferase; RNA cap; Zika virus