Crystal structure of human nicotinamide riboside kinase.
Nicotinamide riboside kinase (NRK) has an important role in the biosynthesis of NAD(+) as well as the activation of tiazofurin and other NR analogs for anticancer therapy. NRK belongs to the deoxynucleoside kinase and nucleoside monophosphate (NMP) kinase superfamily, although the degree of sequence conservation is very low. We report here the crystal structures of human NRK1 in a binary complex with the reaction product nicotinamide mononucleotide (NMN) at 1.5 A resolution and in a ternary complex with ADP and tiazofurin at 2.7 A resolution. The active site is located in a groove between the central parallel beta sheet core and the LID and NMP-binding domains. The hydroxyl groups on the ribose of NR are recognized by Asp56 and Arg129, and Asp36 is the general base of the enzyme. Mutation of residues in the active site can abolish the catalytic activity of the enzyme, confirming the structural observations.
Khan
Javed A
JA
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Xiang
Song
S
Tong
Liang
L
D000244:Adenosine Diphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009537:Nicotinamide Mononucleotide / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012254:Ribavirin / Q000031:analogs & derivatives / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D009537:Nicotinamide Mononucleotide; D012254:Ribavirin; D000244:Adenosine Diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C061783:nicotinamide riboside kinase; C033706:tiazofurin