title: An Unusual Member of the Papain Superfamily: Mapping the Catalytic Cleft of the Marasmius oreades agglutinin (MOA) with a Caspase Inhibitor.
abstract: Papain-like cysteine proteases (PLCPs) constitute the largest group of thiol-based protein degrading enzymes and are characterized by a highly conserved fold. They are found in bacteria, viruses, plants and animals and involved in a number of physiological and pathological processes, parasitic infections and host defense, making them interesting targets for drug design. The Marasmius oreades agglutinin (MOA) is a blood group B-specific fungal chimerolectin with calcium-dependent proteolytic activity. The proteolytic domain of MOA presents a unique structural arrangement, yet mimicking the main structural elements in known PLCPs. Here we present the X-ray crystal structure of MOA in complex with Z-VAD-fmk, an irreversible caspase inhibitor known to cross-react with PLCPs. The structural data allow modeling of the substrate binding geometry and mapping of the fundamental enzyme-substrate interactions. The new information consolidates MOA as a new, yet strongly atypical member of the papain superfamily. The reported complex is the first published structure of a PLCP in complex with the well characterized caspase inhibitor Z-VAD-fmk.
authors.affiliation: Department of Chemistry, University of Oslo, Oslo, Norway.|Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cordara
authors.affiliation: Department of Chemistry, University of Oslo, Oslo, Norway.
authors.forename: André
authors.initials: A
authors.lastname: van Eerde
authors.affiliation: Department of Chemistry, University of Oslo, Oslo, Norway.
authors.forename: Elin M
authors.initials: EM
authors.lastname: Grahn
authors.affiliation: Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Winter
authors.affiliation: Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Goldstein
authors.affiliation: Department of Chemistry, University of Oslo, Oslo, Norway.
authors.forename: Ute
authors.initials: U
authors.lastname: Krengel
mesh_terms: D000373:Agglutinins / Q000737:chemistry*; D061945:Caspase Inhibitors / Q000737:chemistry*; D002384:Catalysis; D055433:Marasmius / Q000201:enzymology*; D010206:Papain / Q000737:chemistry; D017434:Protein Structure, Tertiary
chemical_list: D000373:Agglutinins; D061945:Caspase Inhibitors; D010206:Papain