title: The crystal structure of the Venezuelan equine encephalitis alphavirus nsP2 protease.
abstract: Alphavirus replication and propagation is dependent on the protease activity of the viral nsP2 protein, which cleaves the nsP1234 polyprotein replication complex into functional components. Thus, nsP2 is an attractive target for drug discovery efforts to combat highly pathogenic alphaviruses. Unfortunately, antiviral development has been hampered by a lack of structural information for the nsP2 protease. Here, we report the crystal structure of the nsP2 protease (nsP2pro) from Venezuelan equine encephalitis alphavirus determined at 2.45 A resolution. The protease structure consists of two distinct domains. The nsP2pro N-terminal domain contains the catalytic dyad cysteine and histidine residues organized in a protein fold that differs significantly from any known cysteine protease or protein folds. The nsP2pro C-terminal domain displays structural similarity to S-adenosyl-L-methionine-dependent RNA methyltransferases and provides essential elements that contribute to substrate recognition and may also regulate the structure of the substrate binding cleft.
authors.affiliation: Department of Biochemistry and Molecular Biology and Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Russo
authors.forename: Mark A
authors.initials: MA
authors.lastname: White
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Watowich
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D004666:Encephalitis Virus, Venezuelan Equine / Q000201:enzymology*; D006868:Hydrolysis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
chemical_list: D003546:Cysteine Endopeptidases; C078306:nsP2 proteinase