Prion infection is characterized by the conversion of host cellular prion protein (PrP C ) into disease-related conformers (PrP Sc ) and can be arrested in vivo by passive immunization with anti-PrP monoclonal antibodies. Here, we show that the ability of an antibody to cure prion-infected cells correlates with its binding affinity for PrP C rather than PrP Sc . We have visualized this interaction at the molecular level by determining the crystal structure of human PrP bound to the Fab fragment of monoclonal antibody ICSM 18, which has the highest affinity for PrP C and the highest therapeutic potency in vitro and in vivo. In this crystal structure, human PrP is observed in its native PrP C conformation. Interactions between neighboring PrP molecules in the crystal structure are mediated by close homotypic contacts between residues at position 129 that lead to the formation of a 4-strand intermolecular ␤-sheet. The importance of this residue in mediating protein-protein contact could explain the genetic susceptibility and prion strain selection determined by polymorphic residue 129 in human prion disease, one of the strongest common susceptibility polymorphisms known in any human disease.Creutzfeldt-Jakob disease ͉ PrP-Fab complex ͉ monoclonal antibody ͉ prion therapeutics

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4 Fukuoka Dental College 8-Oxoguanine is produced in the chromosomal DNA, RNA and free nucleotides such as dGTP and GTP by active oxygen species usually formed during cellular metabolic processes. 8-Oxoguanine can mispair with adenine during replication and transcription. Escherichia coli MutT protein prevents replicational and transcriptional errors by hydrolysis of potent mutagenic substrates for DNA and RNA syntheses, 8-oxo-dGTP and 8-oxo-GTP to the corresponding nucleoside monophosphates. Our research purpose is to get detailed insights into the specific recognition for the 8-oxoguanine base and the catalytic mechanism for the hydrolysis of 8-oxo-dGTP and 8-oxo-GTP by the MutT protein. In this study, we have determined the crystal structures of E. coli MutT proteins with and without manganese ions. First, the structure of apo MutT was solved by the MAD method using selenomethionyl MutT protein. Second, the structure of MutT-metal complex was solved by the molecular replacement method using the apo MutT structure. The overall structure of MutT consists of an α + β fold with 6-stranded β-sheet sandwiched between the two α-helices. Three manganese ions bind to a glutamate cluster in Nudix motif (GX5EX7REUXEEXGU) with no significant conformational changes compared with apo MutT.

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