title: Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features.
abstract: The Middle-East Respiratory Syndrome coronavirus (MERS-CoV) causes severe acute pneumonia and renal failure. The MERS-CoV papain-like protease (PL(pro)) is a potential target for the development of antiviral drugs. To facilitate these efforts, we determined the three-dimensional structure of the enzyme by X-ray crystallography. The molecule consists of a ubiquitin-like domain and a catalytic core domain. The catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a solvent-exposed substrate-binding region. The overall structure of the MERS-CoV PL(pro) is similar to that of the corresponding SARS-CoV enzyme, but the architecture of the oxyanion hole and of the S3 as well as the S5 specificity sites differ from the latter. These differences are the likely reason for reduced in vitro peptide hydrolysis and deubiquitinating activities of the MERS-CoV PL(pro), compared to the homologous enzyme from the SARS coronavirus. Introduction of a side-chain capable of oxyanion stabilization through the Leu106Trp mutation greatly enhances the in vitro catalytic activity of the MERS-CoV PL(pro). The unique features observed in the crystal structure of the MERS-CoV PL(pro) should allow the design of antivirals that would not interfere with host ubiquitin-specific proteases.
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; German Center for Infection Research (DZIF), Germany.
authors.forename: Jian
authors.initials: J
authors.lastname: Lei
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; German Center for Infection Research (DZIF), Germany.
authors.forename: Jeroen R
authors.initials: JR
authors.lastname: Mesters
authors.affiliation: Institute of Virology, University of Bonn Medical School, 53127 Bonn, Germany; German Center for Infection Research (DZIF), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Drosten
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; German Center for Infection Research (DZIF), Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Anemüller
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; German Center for Infection Research (DZIF), Germany.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; German Center for Infection Research (DZIF), Germany. Electronic address: hilgenfeld@biochem.uni-luebeck.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Hilgenfeld
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D065207:Middle East Respiratory Syndrome Coronavirus / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010206:Papain / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics
chemical_list: D014764:Viral Proteins; D010206:Papain
keywords: Antiviral drug design; Deubiquitinase; MERS-CoV; Oxyanion hole; Papain-like protease; Zinc finger