title: The structure of ADP-ribose pyrophosphatase reveals the structural basis for the versatility of the Nudix family.
abstract: Regulation of cellular levels of ADP-ribose is important in preventing nonenzymatic ADP-ribosylation of proteins. The Escherichia coli ADP-ribose pyrophosphatase, a Nudix enzyme, catalyzes the hydrolysis of ADP-ribose to ribose-5-P and AMP, compounds that can be recycled as part of nucleotide metabolism. The structures of the apo enzyme, the active enzyme and the complex with ADP-ribose were determined to 1.9 A, 2.7 A and 2.3 A, respectively. The structures reveal a symmetric homodimer with two equivalent catalytic sites, each formed by residues of both monomers, requiring dimerization through domain swapping for substrate recognition and catalytic activity. The structures also suggest a role for the residues conserved in each Nudix subfamily. The Nudix motif residues, folded as a loop-helix-loop tailored for pyrophosphate hydrolysis, compose the catalytic center; residues conferring substrate specificity occur in regions of the sequence removed from the Nudix motif. This segregation of catalytic and recognition roles provides versatility to the Nudix family.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Gabelli
authors.forename: M A
authors.initials: MA
authors.lastname: Bianchet
authors.forename: M J
authors.initials: MJ
authors.lastname: Bessman
authors.forename: L M
authors.initials: LM
authors.lastname: Amzel
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001051:Apoenzymes / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002413:Cations, Divalent / Q000378:metabolism; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins; D006868:Hydrolysis; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011755:Pyrophosphatases / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000096964:Nudix Hydrolases
chemical_list: D000246:Adenosine Diphosphate Ribose; D001051:Apoenzymes; D001426:Bacterial Proteins; D002413:Cations, Divalent; D029968:Escherichia coli Proteins; D008274:Magnesium; D010744:Phosphoric Monoester Hydrolases; D011755:Pyrophosphatases; D000096964:Nudix Hydrolases; C052211:mutT protein, E coli; C019620:ADPribose pyrophosphatase