Structural characterization of the mammalian deoxynucleotide N-hydrolase Rcl and its stabilizing interactions with two inhibitors.
The gene Rcl encodes a deoxynucleoside 5'-monophosphate N-glycosidase that catalyzes the hydrolysis of the N-glycosidic bond of the nucleotide to give deoxyribose 5-phosphate and a nucleobase, preferentially a purine. This enzyme is over-expressed in several cancers, and its rate of expression is correlated to the degree of aggressiveness of tumors, which makes it a new and attractive therapeutic target. We describe here its structural characterization in the presence of two inhibitory substrate mimics. One of these ligands corresponds to the monophosphorylated form of acyclovir, which is used in the clinic. This study reveals an important ligand-induced stabilization of the dimer structure of the enzyme. The original structural features of Rcl will be helpful for designing new inhibitors.
Yang
Yinshan
Y
CNRS, UMR5048, Centre de Biochimie Structurale, Montpellier, France.
Padilla
André
A
Zhang
Chi
C
Labesse
Gilles
G
Kaminski
P Alexandre
PA
D000212:Acyclovir / Q000031:analogs & derivatives / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000235:genetics; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004795:Enzyme Stability; D014644:Genetic Variation; D006157:Guanosine Monophosphate / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid
D004791:Enzyme Inhibitors; D008024:Ligands; D006157:Guanosine Monophosphate; D004247:DNA; C518894:DNPH1 protein, rat; D009699:N-Glycosyl Hydrolases; D000212:Acyclovir