title: Crystal structure of the mouse hepatitis virus ns2 phosphodiesterase domain that antagonizes RNase L activation.
abstract: Prior studies have demonstrated that the mouse hepatitis virus (MHV) A59 strain ns2 protein is a member of the 2H phosphoesterase family and exhibits 2',5'-phosphodiesterase (PDE) activity. During the IFN antiviral response, ns2 cleaves 2',5'-oligoadenylate (2-5A), a key mediator of RNase L activation, thereby subverting the activation of RNase L and evading host innate immunity. However, the mechanism of 2-5A cleavage by ns2 remains unclear. Here, we present the crystal structure of the MHV ns2 PDE domain and demonstrate a PDE fold similar to that of the cellular protein, a kinase anchoring protein 7 central domain (AKAP7(CD)) and rotavirus VP3 carboxy-terminal domain. The structure displays a pair of strictly conserved HxT/Sx motifs and forms a deep, positively charged catalytic groove with β-sheets and an arginine-containing loop. These findings provide insight into the structural basis for 2-5A binding of MHV ns2.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PRChina.
authors.forename: Baokun
authors.initials: B
authors.lastname: Sui
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PRChina.
authors.forename: Junhua
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Babal K
authors.initials: BK
authors.lastname: Jha
authors.affiliation: National Key Laboratory of Crop Improvement, Huazhong Agricultural University, Wuhan 430070, PRChina.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PRChina.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Zhen F
authors.initials: ZF
authors.lastname: Fu
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Weiss
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PRChina.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PRChina.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D020134:Catalytic Domain; D003001:Cloning, Molecular; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004722:Endoribonucleases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D006517:Murine hepatitis virus / Q000737:chemistry* / Q000201:enzymology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012401:Rotavirus / Q000737:chemistry; D040681:Structural Homology, Protein; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C487791:Akap7 protein, mouse; D011994:Recombinant Proteins; D017361:Viral Nonstructural Proteins; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease; D010727:Phosphoric Diester Hydrolases